Medicine › Physiology

Alzheimer's disease research and treatments

Works Count: 91940

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Description

This cluster of papers focuses on the research and mechanisms related to Alzheimer's disease, including the amyloid hypothesis, tau pathology, protein misfolding, neuroinflammation, synaptic dysfunction, oxidative stress, genetic associations, Aß oligomers, neurodegeneration, and therapeutic strategies.

Keywords

Amyloid Hypothesis; Tau Pathology; Protein Misfolding; Neuroinflammation; Synaptic Dysfunction; Oxidative Stress; Genetic Association; Aß Oligomers; Neurodegeneration; Therapeutic Strategies

Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17

1998-06-01

Mike Hutton , Corinne Lendon , Patrizia Rizzu +7 more

Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse

1999-07-01

Dale Schenk , Robin Barbour , Whitney Dunn +7 more

Triple-Transgenic Model of Alzheimer's Disease with Plaques and Tangles

2003-07-01

Salvatore Oddo , Antonella Caccamo , Jason D. Shepherd +7 more

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Phases of Aβ-deposition in the human brain and its relevance for the development of AD

2002-06-25

Dietmar Rudolf Thal , Udo Rüb , M Orantes +1 more

Background: The deposition of the amyloid β protein (Aβ) is a histopathologic hallmark of AD. The regions of the medial temporal lobe (MTL) are hierarchically involved in Aβ-deposition. Objective: To … Background: The deposition of the amyloid β protein (Aβ) is a histopathologic hallmark of AD. The regions of the medial temporal lobe (MTL) are hierarchically involved in Aβ-deposition. Objective: To clarify whether there is a hierarchical involvement of the regions of the entire brain as well and whether there are differences in the expansion of Aβ-pathology between clinically proven AD cases and nondemented cases with AD-related pathology, the authors investigated 47 brains from demented and nondemented patients with AD-related pathology covering all phases of β-amyloidosis in the MTL (AβMTL phases) and four control brains without any AD-related pathology. Methods: Aβ deposits were detected by the use of the Campbell-Switzer silver technique and by immunohistochemistry in sections covering all brain regions and brainstem nuclei. It was analyzed how often distinct regions exhibited Aβ deposits. Results: In the first of five phases in the evolution of β-amyloidosis Aβ deposits are found exclusively in the neocortex. The second phase is characterized by the additional involvement of allocortical brain regions. In phase 3, diencephalic nuclei, the striatum, and the cholinergic nuclei of the basal forebrain exhibit Aβ deposits as well. Several brainstem nuclei become additionally involved in phase 4. Phase 5, finally, is characterized by cerebellar Aβ-deposition. The 17 clinically proven AD cases exhibit Aβ-phases 3, 4, or 5. The nine nondemented cases with AD-related Aβ pathology show Aβ-phases 1, 2, or 3. Conclusions: Aβ-deposition in the entire brain follows a distinct sequence in which the regions are hierarchically involved. Aβ-deposition, thereby, expands anterogradely into regions that receive neuronal projections from regions already exhibiting Aβ. There are also indications that clinically proven AD cases with full-blown β-amyloidosis may be preceded in early stages by nondemented cases exhibiting AD-related Aβ pathology.

Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide

2007-01-24

Christian Haass , Dennis J. Selkoe

Effects of Age, Sex, and Ethnicity on the Association Between Apolipoprotein E Genotype and Alzheimer Disease

1997-10-22

Lindsay A. Farrer

<h3>Objective.</h3> —To examine more closely the association between apolipoprotein E (APOE) genotype and Alzheimer disease (AD) by age and sex in populations of various ethnic and racial denominations. <h3>Data Sources.</h3> … <h3>Objective.</h3> —To examine more closely the association between apolipoprotein E (APOE) genotype and Alzheimer disease (AD) by age and sex in populations of various ethnic and racial denominations. <h3>Data Sources.</h3> —Forty research teams contributed data onAPOEgenotype, sex, age at disease onset, and ethnic background for 5930 patients who met criteria for probable or definite AD and 8607 controls without dementia who were recruited from clinical, community, and brain bank sources. <h3>Main Outcome Measures.</h3> —Odds ratios (ORs) and 95% confidence intervals (Cls) for AD, adjusted for age and study and stratified by major ethnic group (Caucasian, African American, Hispanic, and Japanese) and source, were computed forAPOEgenotypes ∈2/∈2,∈2/∈3,∈2/∈4,∈3/∈4 and ∈4/∈4 relative to the ∈3/∈3 group. The influence of age and sex on the OR for each genotype was assessed using logistic regression procedures. <h3>Results.</h3> —Among Caucasian subjects from clinic- or autopsy-based studies, the risk of AD was significantly increased for people with genotypes ∈2/∈4 (OR=2.6, 95% Cl=1.6-4.0), ∈3/∈4 (OR=3.2, 95% Cl=2.8-3.8), and ∈4/∈4 (OR=14.9, 95% CI=10.8-20.6); whereas, the ORs were decreased for people with genotypes ∈2/∈2 (OR=0.6, 95% Cl=0.2-2.0) and ∈2/∈3 (OR=0.6, 95% Cl=0.5-0.8). TheAPOE∈4-AD association was weaker among African Americans and Hispanics, but there was significant heterogeneity in ORs among studies of African Americans (P<.03). TheAPOE∈4—AD association in Japanese subjects was stronger than in Caucasian subjects (∈3/∈4: OR=5.6, 95% Cl=3.9-8.0; ∈4/∈4: OR=33.1, 95% Cl=13.6-80.5). The ∈2/∈3 genotype appears equally protective across ethnic groups. We also found that among Caucasians,APOEgenotype distributions are similar in groups of patients with AD whose diagnoses were determined clinically or by autopsy. In addition, we found that theAPOE∈4 effect is evident at all ages between 40 and 90 years but diminishes after age 70 years and that the risk of AD associated with a given genotype varies with sex. <h3>Conclusions.</h3> —TheAPOE∈4 allele represents a major risk factor for AD in all ethnic groups studied, across all ages between 40 and 90 years, and in both men and women. The association betweenAPOE∈4 and AD in African Americans requires clarification, and the attenuated effect ofAPOE∈4 in Hispanics should be investigated further.

Physical basis of cognitive alterations in alzheimer's disease: Synapse loss is the major correlate of cognitive impairment

1991-10-01

Robert D. Terry , Eliezer Masliah , David P. Salmon +5 more

Abstract We present here both linear regressions and multivariate analyses correlating three global neuropsychological tests with a number of structural and neurochemical measurements performed on a prospective series of 15 … Abstract We present here both linear regressions and multivariate analyses correlating three global neuropsychological tests with a number of structural and neurochemical measurements performed on a prospective series of 15 patients with Alzheimer's disease and 9 neuropathologically normal subjects. The statistical data show only weak correlations between psychometric indices and plaques and tangles, but the density of neocortical synapses measured by a new immunocytochemical/densitometric technique reveals very powerful correlations with all three psychological assays. Multivariate analysis by stepwise regression produced a model including midfrontal and inferior parietal synapse density, plus inferior parietal plaque counts with a correlation coefficient of 0.96 for Mattis's Dementia Rating Scale. Plaque density contributed only 26% of that strength.

Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers

2013-01-16

Clifford R. Jack , David S. Knopman , William J. Jagust +7 more

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Association of apolipoprotein E allele ϵ4 with late‐onset familial and sporadic Alzheimer's disease

1993-08-01

Ann M. Saunders , Warren J. Strittmatter , D. E. Schmechel +7 more

Apolipoprotein E, type ϵ4 allele (APOE ϵ4), is associated with late-onset familial Alzheimer9s disease (AD). There is high avidity and specific binding of amyloid β-peptide with the protein ApoE. To … Apolipoprotein E, type ϵ4 allele (APOE ϵ4), is associated with late-onset familial Alzheimer9s disease (AD). There is high avidity and specific binding of amyloid β-peptide with the protein ApoE. To test the hypothesis that late-onset familial AD may represent the clustering of sporadic AD in families large enough to be studied, we extended the analyses of APOE alleles to several series of sporadic AD patients. APOE ϵ4 is significantly associated with a series of probable sporadic AD patients (0.36 ± 0.042, AD, versus 0.16 ± 0.027, controls [allele frequency estimate ± standard error], p = 0.00031). Spouse controls did not differ from CEPH grandparent controls from the Centre d9Etude du Polymorphisme Humain (CEPH) or from literature controls. A large combined series of autopsy-documented sporadic AD patients also demonstrated highly significant association with the APOE ϵ4 allele (0.40 ± 0.026, p ≤ 0.00001). These data support the involvement of ApoE ϵ4 in the pathogenesis of late-onset familial and sporadic AD. ApoE isoforms may play an important role in the metabolism of β-peptide, and APOE ϵ4 may operate as a susceptibility gene (risk factor) for the clinical expression of AD.

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Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice

1996-10-04

Karen Hsiao , Paul F. Chapman , Steven P. Nilsen +5 more

Transgenic mice overexpressing the 695-amino acid isoform of human Alzheimer β-amyloid (Aβ) precursor protein containing a Lys 670 → Asn, Met 671 → Leu mutation had normal learning and memory … Transgenic mice overexpressing the 695-amino acid isoform of human Alzheimer β-amyloid (Aβ) precursor protein containing a Lys 670 → Asn, Met 671 → Leu mutation had normal learning and memory in spatial reference and alternation tasks at 3 months of age but showed impairment by 9 to 10 months of age. A fivefold increase in Aβ(1-40) and a 14-fold increase in Aβ(1-42/43) accompanied the appearance of these behavioral deficits. Numerous Aβ plaques that stained with Congo red dye were present in cortical and limbic structures of mice with elevated amounts of Aβ. The correlative appearance of behavioral, biochemical, and pathological abnormalities reminiscent of Alzheimer's disease in these transgenic mice suggests new opportunities for exploring the pathophysiology and neurobiology of this disease.

Protein aggregation and neurodegenerative disease

2004-07-01

Christopher A. Ross , Michelle A. Poirier

Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease.

1993-03-01

Warren J. Strittmatter , Ann M. Saunders , D. E. Schmechel +4 more

Apolipoprotein E is immunochemically localized to the senile plaques, vascular amyloid, and neurofibrillary tangles of Alzheimer disease. In vitro, apolipoprotein E in cerebrospinal fluid binds to synthetic beta A4 peptide … Apolipoprotein E is immunochemically localized to the senile plaques, vascular amyloid, and neurofibrillary tangles of Alzheimer disease. In vitro, apolipoprotein E in cerebrospinal fluid binds to synthetic beta A4 peptide (the primary constituent of the senile plaque) with high avidity. Amino acids 12-28 of the beta A4 peptide are required. The gene for apolipoprotein E is located on chromosome 19q13.2, within the region previously associated with linkage of late-onset familial Alzheimer disease. Analysis of apolipoprotein E alleles in Alzheimer disease and controls demonstrated that there was a highly significant association of apolipoprotein E type 4 allele (APOE-epsilon 4) and late-onset familial Alzheimer disease. The allele frequency of the APOE-epsilon 4 in 30 random affected patients, each from a different Alzheimer disease family, was 0.50 +/- 0.06; the allele frequency of APOE-epsilon 4 in 91 age-matched unrelated controls was 0.16 +/- 0.03 (Z = 2.44, P = 0.014). A functional role of the apolipoprotein E-E4 isoform in the pathogenesis of late-onset familial Alzheimer disease is suggested.

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Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein

1984-05-01

George G. Glenner , Caine W. Wong

The molecular pathology of Alzheimer's disease

1991-04-01

Dennis J. Selkoe

Gene Dose of Apolipoprotein E Type 4 Allele and the Risk of Alzheimer's Disease in Late Onset Families

1993-08-13

Elizabeth H. Corder , Ann M. Saunders , Warren J. Strittmatter +6 more

The apolipoprotein E type 4 allele ( APOE -ε4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from … The apolipoprotein E type 4 allele ( APOE -ε4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE -ε4 alleles in 42 families with late onset AD. Thus APOE -ε4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE -ε4 was virtually sufficient to cause AD by age 80.

Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology.

1986-07-01

Inge Grundke‐Iqbal , Khurshid Iqbal , Y C Tung +3 more

A monoclonal antibody to the microtubule-associated protein tau (tau) labeled some neurofibrillary tangles and plaque neurites, the two major locations of paired-helical filaments (PHF), in Alzheimer disease brain. The antibody … A monoclonal antibody to the microtubule-associated protein tau (tau) labeled some neurofibrillary tangles and plaque neurites, the two major locations of paired-helical filaments (PHF), in Alzheimer disease brain. The antibody also labeled isolated PHF that had been repeatedly washed with NaDodSO4. Dephosphorylation of the tissue sections with alkaline phosphatase prior to immunolabeling dramatically increased the number of tangles and plaques recognized by the antibody. The plaque core amyloid was not stained in either dephosphorylated or nondephosphorylated tissue sections. On immunoblots PHF polypeptides were labeled readily only when dephosphorylated. In contrast, a commercially available monoclonal antibody to a phosphorylated epitope of neurofilaments that labeled the tangles and the plaque neurites in tissue did not label any PHF polypeptides on immunoblots. The PHF polypeptides, labeled with the monoclonal antibody to tau, electrophoresed with those polypeptides recognized by antibodies to isolated PHF. The antibody to tau-labeled microtubules from normal human brains assembled in vitro but identically treated Alzheimer brain preparations had to be dephosphorylated to be completely recognized by this antibody. These findings suggest that tau in Alzheimer brain is an abnormally phosphorylated protein component of PHF.

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Neurodegenerative diseases and oxidative stress

2004-03-01

Kevin J. Barnham , Colin L. Masters , Ashley I. Bush

Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease

1995-06-01

Robin Sherrington , Е. И. Рогаев , Y. Liang +7 more

Amyloid plaque core protein in Alzheimer disease and Down syndrome.

1985-06-01

Colin L. Masters , G. Simms , Nicola A. Weinman +3 more

We have purified and characterized the cerebral amyloid protein that forms the plaque core in Alzheimer disease and in aged individuals with Down syndrome. The protein consists of multimeric aggregates … We have purified and characterized the cerebral amyloid protein that forms the plaque core in Alzheimer disease and in aged individuals with Down syndrome. The protein consists of multimeric aggregates of a polypeptide of about 40 residues (4 kDa). The amino acid composition, molecular mass, and NH2-terminal sequence of this amyloid protein are almost identical to those described for the amyloid deposited in the congophilic angiopathy of Alzheimer disease and Down syndrome, but the plaque core proteins have ragged NH2 termini. The shared 4-kDa subunit indicates a common origin for the amyloids of the plaque core and of the congophilic angiopathy. There are superficial resemblances between the solubility characteristics of the plaque core and some of the properties of scrapie infectivity, but there are no similarities in amino acid sequences between the plaque core and scrapie polypeptides.

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Neuropathological stageing of Alzheimer-related changes

1991-09-01

Heiko Braak , Eva Braak

Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease

1991-02-01

Alison Goate , Marie‐Christine Chartier‐Harlin , Michael Mullan +7 more

RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory

2006-03-15

Sylvain Lesné , Ming Teng Koh , Linda Kotilinek +5 more

Pathways towards and away from Alzheimer's disease

2004-08-04

Mark P. Mattson

The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor

1987-02-01

Jie Kang , Hans-Georg Lemaire , Axel Unterbeck +6 more

Amyloid Oligomers Exacerbate Tau Pathology in a Mouse Model of Tauopathy

2012-07-10

Maj-Linda B. Selenica , Milene L. Brownlow , Jeffy P. Jimenez +5 more

We have extensively analyzed the biochemical and histochemical profiles of the tau protein from the rTg4510 transgenic mouse model in which the animals uniquely develop forebrain tau pathologies similar to … We have extensively analyzed the biochemical and histochemical profiles of the tau protein from the rTg4510 transgenic mouse model in which the animals uniquely develop forebrain tau pathologies similar to those found in human tauopathies. Levels of several soluble phosphorylated tau species were highest at 1 month relative to later time points, suggesting that certain tau hyperphosphorylation events were insufficient to drive tangle formation in young mice. Despite a robust, pre-tangle-like accumulation of phospho-tau in 1-month-old mice, this material was cleared by 3 months, indicating that the young mouse brain either fails to facilitate tau insolubility or possesses an enhanced ability to clear tau relative to the adult. We also found that while heat shock protein expression increased with normal aging, this process was accelerated in rTg4510 mice. Moreover, by exploiting an exon 10 (-) specific antibody, we demonstrated that endogenous mouse tau turnover was slowed in response to human tau over-expression, and that this endogenous tau adopted disease-related properties. These data suggest that a younger brain fails to develop lasting tau pathology despite elevated levels of phosphorylated tau, perhaps because of reduced expression of stress-related proteins. Moreover, we show that the active production of small amounts of abnormal tau protein facilitates dysfunction and accumulation of otherwise normal tau, a significant implication for the pathogenesis of patients with Alzheimer's disease.

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Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry

2006-08-11

Heiko Braak , Irina Alafuzoff , Thomas Arzberger +2 more

Assessment of Alzheimer's disease (AD)-related neurofibrillary pathology requires a procedure that permits a sufficient differentiation between initial, intermediate, and late stages. The gradual deposition of a hyperphosphorylated tau protein within … Assessment of Alzheimer's disease (AD)-related neurofibrillary pathology requires a procedure that permits a sufficient differentiation between initial, intermediate, and late stages. The gradual deposition of a hyperphosphorylated tau protein within select neuronal types in specific nuclei or areas is central to the disease process. The staging of AD-related neurofibrillary pathology originally described in 1991 was performed on unconventionally thick sections (100 mum) using a modern silver technique and reflected the progress of the disease process based chiefly on the topographic expansion of the lesions. To better meet the demands of routine laboratories this procedure is revised here by adapting tissue selection and processing to the needs of paraffin-embedded sections (5-15 mum) and by introducing a robust immunoreaction (AT8) for hyperphosphorylated tau protein that can be processed on an automated basis. It is anticipated that this revised methodological protocol will enable a more uniform application of the staging procedure.

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The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics

2002-07-19

John Hardy , Dennis J. Selkoe

It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid beta-peptide (Abeta) in plaques … It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid beta-peptide (Abeta) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Abeta in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Abeta production and Abeta clearance.

Neuropathological Alterations in Alzheimer Disease

2011-09-01

Alberto Serrano‐Pozo , Matthew P. Frosch , Eliezer Masliah +1 more

Alberto Serrano-Pozo1, Matthew P. Frosch1,2, Eliezer Masliah3 and Bradley T. Hyman1 Alzheimer Research Unit of the MassGeneral Institute for Neurodegenerative Disease, Department of Neurology of the Massachusetts General Hospital, and … Alberto Serrano-Pozo1, Matthew P. Frosch1,2, Eliezer Masliah3 and Bradley T. Hyman1 Alzheimer Research Unit of the MassGeneral Institute for Neurodegenerative Disease, Department of Neurology of the Massachusetts General Hospital, and Harvard Medical School, Charlestown, Massachusetts 02129-4404 C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Boston, Massachusetts 02114 Department of Neuroscience and Department of Pathology, University of California-San Diego School of Medicine, La Jolla, California 92093-0624 Correspondence: bhyman{at}partners.org

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Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory

2008-06-22

Ganesh M. Shankar , Shaomin Li , Tapan Mehta +7 more

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Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease

2013-10-27

Jean‐Charles Lambert , Carla A. Ibrahim‐Verbaas , Denise Harold +7 more

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Inflammation and Alzheimer's disease

2000-06-01

Haruhiko Akiyama , Steven W. Barger , Scott R. Barnum +7 more

Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis

2003-04-17

Rakez Kayed , Elizabeth Head , Jennifer L. Thompson +4 more

Soluble oligomers are common to most amyloids and may represent the primary toxic species of amyloids, like the Abeta peptide in Alzheimer's disease (AD). Here we show that all of … Soluble oligomers are common to most amyloids and may represent the primary toxic species of amyloids, like the Abeta peptide in Alzheimer's disease (AD). Here we show that all of the soluble oligomers tested display a common conformation-dependent structure that is unique to soluble oligomers regardless of sequence. The in vitro toxicity of soluble oligomers is inhibited by oligomer-specific antibody. Soluble oligomers have a unique distribution in human AD brain that is distinct from fibrillar amyloid. These results indicate that different types of soluble amyloid oligomers have a common structure and suggest they share a common mechanism of toxicity.

Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging‐Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease

2011-04-22

Reisa A. Sperling , Paul Aisen , Laurel Beckett +7 more

The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long “preclinical” phase of AD would provide a critical opportunity … The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long “preclinical” phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from “normal” cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease‐modifying therapies may be most efficacious.

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β-Secretase Cleavage of Alzheimer's Amyloid Precursor Protein by the Transmembrane Aspartic Protease BACE

1999-10-22

Robert Vassar , Brian D. Bennett , Safura Babu‐Khan +7 more

Cerebral deposition of amyloid β peptide (Aβ) is an early and critical feature of Alzheimer's disease. Aβ generation depends on proteolytic cleavage of the amyloid precursor protein (APP) by two … Cerebral deposition of amyloid β peptide (Aβ) is an early and critical feature of Alzheimer's disease. Aβ generation depends on proteolytic cleavage of the amyloid precursor protein (APP) by two unknown proteases: β-secretase and γ-secretase. These proteases are prime therapeutic targets. A transmembrane aspartic protease with all the known characteristics of β-secretase was cloned and characterized. Overexpression of this protease, termed BACE (for beta-site APP-cleaving enzyme) increased the amount of β-secretase cleavage products, and these were cleaved exactly and only at known β-secretase positions. Antisense inhibition of endogenous BACE messenger RNA decreased the amount of β-secretase cleavage products, and purified BACE protein cleaved APP-derived substrates with the same sequence specificity as β-secretase. Finally, the expression pattern and subcellular localization of BACE were consistent with that expected for β-secretase. Future development of BACE inhibitors may prove beneficial for the treatment of Alzheimer's disease.

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Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy

2013-01-08

Chia‐Chen Liu , Takahisa Kanekiyo , Huaxi Xu +1 more

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Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo

2002-04-01

Dominic M. Walsh , Igor Klyubin , Julia V. Fadeeva +5 more

Diffusible, nonfibrillar ligands derived from Aβ 1–42 are potent central nervous system neurotoxins

1998-05-26

Mary P. Lambert , Avlin Barlow , Brett A. Chromy +7 more

Aβ 1–42 is a self-associating peptide whose neurotoxic derivatives are thought to play a role in Alzheimer’s pathogenesis. Neurotoxicity of amyloid β protein (Aβ) has been attributed to its fibrillar … Aβ 1–42 is a self-associating peptide whose neurotoxic derivatives are thought to play a role in Alzheimer’s pathogenesis. Neurotoxicity of amyloid β protein (Aβ) has been attributed to its fibrillar forms, but experiments presented here characterize neurotoxins that assemble when fibril formation is inhibited. These neurotoxins comprise small diffusible Aβ oligomers (referred to as ADDLs, for Aβ-derived diffusible ligands), which were found to kill mature neurons in organotypic central nervous system cultures at nanomolar concentrations. At cell surfaces, ADDLs bound to trypsin-sensitive sites and surface-derived tryptic peptides blocked binding and afforded neuroprotection. Germ-line knockout of Fyn, a protein tyrosine kinase linked to apoptosis and elevated in Alzheimer’s disease, also was neuroprotective. Remarkably, neurological dysfunction evoked by ADDLs occurred well in advance of cellular degeneration. Without lag, and despite retention of evoked action potentials, ADDLs inhibited hippocampal long-term potentiation, indicating an immediate impact on signal transduction. We hypothesize that impaired synaptic plasticity and associated memory dysfunction during early stage Alzheimer’s disease and severe cellular degeneration and dementia during end stage could be caused by the biphasic impact of Aβ-derived diffusible ligands acting upon particular neural signal transduction pathways.

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Protein Misfolding, Functional Amyloid, and Human Disease

2006-04-07

Fabrizio Chiti , Christopher M. Dobson

Peptides or proteins convert under some conditions from their soluble forms into highly ordered fibrillar aggregates. Such transitions can give rise to pathological conditions ranging from neurodegenerative disorders to systemic … Peptides or proteins convert under some conditions from their soluble forms into highly ordered fibrillar aggregates. Such transitions can give rise to pathological conditions ranging from neurodegenerative disorders to systemic amyloidoses. In this review, we identify the diseases known to be associated with formation of fibrillar aggregates and the specific peptides and proteins involved in each case. We describe, in addition, that living organisms can take advantage of the inherent ability of proteins to form such structures to generate novel and diverse biological functions. We review recent advances toward the elucidation of the structures of amyloid fibrils and the mechanisms of their formation at a molecular level. Finally, we discuss the relative importance of the common main-chain and side-chain interactions in determining the propensities of proteins to aggregate and describe some of the evidence that the oligomeric fibril precursors are the primary origins of pathological behavior.

Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound‐B

2004-01-21

William E. Klunk , Henry Engler , Agneta Nordberg +7 more

This report describes the first human study of a novel amyloid-imaging positron emission tomography (PET) tracer, termed Pittsburgh Compound-B (PIB), in 16 patients with diagnosed mild AD and 9 controls. … This report describes the first human study of a novel amyloid-imaging positron emission tomography (PET) tracer, termed Pittsburgh Compound-B (PIB), in 16 patients with diagnosed mild AD and 9 controls. Compared with controls, AD patients typically showed marked retention of PIB in areas of association cortex known to contain large amounts of amyloid deposits in AD. In the AD patient group, PIB retention was increased most prominently in frontal cortex (1.94-fold, p = 0.0001). Large increases also were observed in parietal (1.71-fold, p = 0.0002), temporal (1.52-fold, p = 0.002), and occipital (1.54-fold, p = 0.002) cortex and the striatum (1.76-fold, p = 0.0001). PIB retention was equivalent in AD patients and controls in areas known to be relatively unaffected by amyloid deposition (such as subcortical white matter, pons, and cerebellum). Studies in three young (21 years) and six older healthy controls (69.5 +/- 11 years) showed low PIB retention in cortical areas and no significant group differences between young and older controls. In cortical areas, PIB retention correlated inversely with cerebral glucose metabolism determined with 18F-fluorodeoxyglucose. This relationship was most robust in the parietal cortex (r = -0.72; p = 0.0001). The results suggest that PET imaging with the novel tracer, PIB, can provide quantitative information on amyloid deposits in living subjects.

Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade

2009-12-15

Clifford R. Jack , David S. Knopman , William J. Jagust +5 more

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Alzheimer's Disease Is a Synaptic Failure

2002-10-24

Dennis J. Selkoe

In its earliest clinical phase, Alzheimer's disease characteristically produces a remarkably pure impairment of memory. Mounting evidence suggests that this syndrome begins with subtle alterations of hippocampal synaptic efficacy prior … In its earliest clinical phase, Alzheimer's disease characteristically produces a remarkably pure impairment of memory. Mounting evidence suggests that this syndrome begins with subtle alterations of hippocampal synaptic efficacy prior to frank neuronal degeneration, and that the synaptic dysfunction is caused by diffusible oligomeric assemblies of the amyloid β protein.

Alzheimer's Disease: Genes, Proteins, and Therapy

2001-04-01

Dennis J. Selkoe

Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association … Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association cortices. In turn, new insights into fundamental aspects of protein biology have resulted from research on the disease. This beneficial interplay between basic and applied cell biology is well illustrated by advances in understanding the genotype-to-phenotype relationships of familial Alzheimer's disease. All four genes definitively linked to inherited forms of the disease to date have been shown to increase the production and/or deposition of amyloid β-protein in the brain. In particular, evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the β-amyloid precursor protein by the protease called γ-secretase has spurred progress toward novel therapeutics. The finding that presenilin itself may be the long-sought γ-secretase, coupled with the recent identification of β-secretase, has provided discrete biochemical targets for drug screening and development. Alternate and novel strategies for inhibiting the early mechanism of the disease are also emerging. The progress reviewed here, coupled with better ability to diagnose the disease early, bode well for the successful development of therapeutic and preventative drugs for this major public health problem.

Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation

2006-10-04

Holly D. Oakley , Sarah L. Cole , Sreemathi Logan +7 more

Mutations in the genes for amyloid precursor protein (APP) and presenilins (PS1, PS2) increase production of β-amyloid 42 (Aβ 42 ) and cause familial Alzheimer's disease (FAD). Transgenic mice that … Mutations in the genes for amyloid precursor protein (APP) and presenilins (PS1, PS2) increase production of β-amyloid 42 (Aβ 42 ) and cause familial Alzheimer's disease (FAD). Transgenic mice that express FAD mutant APP and PS1 overproduce Aβ 42 and exhibit amyloid plaque pathology similar to that found in AD, but most transgenic models develop plaques slowly. To accelerate plaque development and investigate the effects of very high cerebral Aβ 42 levels, we generated APP/PS1 double transgenic mice that coexpress five FAD mutations (5XFAD mice) and additively increase Aβ 42 production. 5XFAD mice generate Aβ 42 almost exclusively and rapidly accumulate massive cerebral Aβ 42 levels. Amyloid deposition (and gliosis) begins at 2 months and reaches a very large burden, especially in subiculum and deep cortical layers. Intraneuronal Aβ 42 accumulates in 5XFAD brain starting at 1.5 months of age (before plaques form), is aggregated (as determined by thioflavin S staining), and occurs within neuron soma and neurites. Some amyloid deposits originate within morphologically abnormal neuron soma that contain intraneuronal Aβ. Synaptic markers synaptophysin, syntaxin, and postsynaptic density-95 decrease with age in 5XFAD brain, and large pyramidal neurons in cortical layer 5 and subiculum are lost. In addition, levels of the activation subunit of cyclin-dependent kinase 5, p25, are elevated significantly at 9 months in 5XFAD brain, although an upward trend is observed by 3 months of age, before significant neurodegeneration or neuron loss. Finally, 5XFAD mice have impaired memory in the Y-maze. Thus, 5XFAD mice rapidly recapitulate major features of AD amyloid pathology and may be useful models of intraneuronal Aβ 42 -induced neurodegeneration and amyloid plaque formation.

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Clinical and Biomarker Changes in Dominantly Inherited Alzheimer's Disease

2012-07-11

Randall J. Bateman , Chengjie Xiong , Tammie L.S. Benzinger +7 more

The order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a predictable age … The order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease.

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The amyloid hypothesis of Alzheimer's disease at 25 years

2016-03-29

Dennis J. Selkoe , John Hardy

Review29 March 2016Open Access The amyloid hypothesis of Alzheimer's disease at 25 years Dennis J Selkoe Dennis J Selkoe Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and … Review29 March 2016Open Access The amyloid hypothesis of Alzheimer's disease at 25 years Dennis J Selkoe Dennis J Selkoe Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA Search for more papers by this author John Hardy Corresponding Author John Hardy Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK Search for more papers by this author Dennis J Selkoe Dennis J Selkoe Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA Search for more papers by this author John Hardy Corresponding Author John Hardy Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK Search for more papers by this author Author Information Dennis J Selkoe1,‡ and John Hardy 2,‡ 1Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA 2Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK ‡These authors contributed equally to this work *Corresponding author. Tel: +44 203 108 7466; E-mail: [email protected] EMBO Mol Med (2016)8:595-608https://doi.org/10.15252/emmm.201606210 See the Glossary for abbreviations used in this article. PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions Figures & Info Abstract Despite continuing debate about the amyloid β-protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer's disease (AD). Confirmation that presenilin is the catalytic site of γ-secretase has provided a linchpin: all dominant mutations causing early-onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild-type APP gene in Down's syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD. Apolipoprotein E4, which predisposes to AD in > 40% of cases, has been found to impair Aβ clearance from the brain. Soluble oligomers of Aβ42 isolated from AD patients' brains can decrease synapse number, inhibit long-term potentiation, and enhance long-term synaptic depression in rodent hippocampus, and injecting them into healthy rats impairs memory. The human oligomers also induce hyperphosphorylation of tau at AD-relevant epitopes and cause neuritic dystrophy in cultured neurons. Crossing human APP with human tau transgenic mice enhances tau-positive neurotoxicity. In humans, new studies show that low cerebrospinal fluid (CSF) Aβ42 and amyloid-PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in post hoc analyses of mild AD subjects. Although many factors contribute to AD pathogenesis, Aβ dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target. Glossary Microgliosis early non-specific proliferation and migration of microglial cells, macrophage-like cells in the central nervous system, as the first response to brain damage. Astrocytosis final response to brain damage and injury with proliferation of astrocytes, a type of glial cell responsible for maintaining extracellular ion and neurotransmitter concentrations, modulating synapse function, and forming the blood–brain barrier. Neurofibrillary tangles accumulation of hyperphosphorylated tau protein, commonly found in Alzheimer's disease, that aggregates inside nerve cell bodies, also known as dystrophic neurites. Plaque deposition aggregates of amyloid fibrils that are deposited outside neurons in dense formations, also known as senile plaques or neuritic plaques. FAD familial AD caused by inherited mutations in APP and presenilin (typically early-onset) by opposition to "sporadic" or late-onset AD Introduction Few problems in modern biomedicine have garnered as much scientific interest and public concern as has Alzheimer's disease. Virtually unknown to the general public four decades ago, AD has risen in prevalence to an estimated 40 million patients worldwide. The true number must be much higher, given the increasing recognition that the disease begins in the brain at least 2–3 decades before one first forgets the name of a grandchild or where one has parked one's car. Since molecular studies of AD began in earnest in the early 1980s, thousands of scientists and healthcare professionals have delved into all aspects of this complex, multifactorial syndrome, hoping to help patients now and prevent others from developing it in the future. Although the progressive buildup of amyloids of diverse protein composition in various systemic organs has been known to cause devastating diseases for more than a century, the idea put forward by George Glenner (Glenner & Wong, 1984) that the particular amyloidogenic protein accumulating in AD (Aβ) could be causative has met with considerable skepticism over the ensuing years. Precisely why this idea has been so controversial is not clear (Selkoe, 2011), but the steady accrual of data from many preclinical and clinical studies has increasingly supported it. The amyloid (or Aβ) hypothesis (Beyreuther & Masters, 1991; Hardy & Allsop, 1991; Selkoe, 1991; Hardy & Higgins, 1992) has become the dominant model of AD pathogenesis and is guiding the development of potential treatments. We reviewed the evidence for this hypothesis (Fig 1) a dozen years ago (Hardy & Selkoe, 2002). Space precludes a full examination here of the enormous literature on Aβ since that review; a monograph on AD pathobiology contains many details (Selkoe et al, 2012). But in the context of continuing concern about the concept and yet the recent emergence of apparently positive clinical trial data, a critical analysis of the latest developments in laboratory and clinic is warranted and timely. We review here numerous new developments since our prior review of this hypothesis, on which ever-increasing scientific effort is being expended. We also summarize the salient findings over three decades that undergird the amyloid hypothesis (Box 1), and we discuss several alternative concepts or concerns that have been counterposed to it (Table 1). Box 1: Evidence supporting a key role for Aβ dyshomeostasis in initiating AD All AD patients undergo progressive Aβ deposition followed by surrounding neuritic and glial cytopathology in brain regions serving memory and cognition. Mutations within and immediately flanking the Aβ region of APP cause aggressive forms of FAD. Humans with trisomy 21 (Down's syndrome) harbor 3 copies of APP and invariably develop neuropathologically typical AD. Those who die in their early-to-mid teens (from other causes) show abundant diffuse Aβ plaques without neuritic dystrophy, microgliosis, astrocytosis, and tangle formation, all of which accrue gradually in such subjects in the late teens and beyond. Inheritance of a missense mutation in APP that decreases the production and aggregation of Aβ lifelong protects against AD and age-related cognitive decline. Missense mutations in presenilin 1 or 2 are the most common cause of early-onset AD, and presenilin is the catalytic subunit of γ-secretase. The mutations result in relative increases in the production of Aβ42/43 peptides. These hydrophobic species self-aggregate, leading to profound Aβ deposition in mid-life. ApoE4 carriers were once included in typical late-onset AD. This allele was found to markedly increase AD risk and decrease brain clearance of Aβ, leading to excess Aβ aggregation and typical downstream AD neuropathology. Aβ42 oligomers isolated from typical (late-onset) AD brains decrease synapse density, inhibit LTP, and enhance long-term synaptic depression in rodent hippocampus, and their intraventricular injection impairs memory in healthy adult rats. Human Aβ42 oligomers induce tau hyperphosphorylation at AD-relevant epitopes and cause neuritic dystrophy in cultured rat neurons; co-administering Aβ antibodies fully prevents this. Aβ oligomers occur in a penumbra around many neuritic plaques. Accordingly, synapse decreases occur in a centrifugal gradient: less abnormality at longer distances from the plaque edge. Based on many human biomarker studies, low CSF Aβ42 and positive amyloid-PET scans precede other AD-related changes (increased CSF tau, decreased cerebral glucose metabolism, brain atrophy, clinical dementia) by years. Trials of 3 different Aβ monoclonal antibodies (solanezumab, crenezumab, and aducanumab) have suggested slowing of cognitive decline in post hoc analyses of mild (but not moderate) AD patients. Other amyloidogenic proteins have been proven to cause progressive human organ failure, and therapeutic lowering of the amyloid or its precursor protein yields therapeutic benefits in patients. Figure 1. The sequence of major pathogenic events leading to AD proposed by the amyloid cascade hypothesisThe curved blue arrow indicates that Aβ oligomers may directly injure the synapses and neurites of brain neurons, in addition to activating microglia and astrocytes. Download figure Download PowerPoint Table 1. Findings that appear to undercut the amyloid hypothesis of AD and counterarguments that could explain these discrepancies Findings Counterarguments Amyloid plaque burden correlates much less well with degree of cognitive impairment than do neurofibrillary tangle counts Aβ deposits appear to be a very early and widespread event that is distant to the clinical dementia and can lead to many downstream cellular and molecular changes (e.g., microgliosis, neuritic dystrophy, tangles, etc.) that are more proximate to and causative of neuronal dysfunction Many humans show sometimes abundant Aβ deposits at death but were not noticeably demented Some or many of these deposits are diffuse plaques (not rich in abnormal neurites and glia); the patients were often not tested rigorously before death; and Aβ oligomer levels per plaque are much lower than in AD brains (Esparza et al, 2013), suggesting that plaques can effectively sequester oligomers in a non-diffusible, less neurotoxic state, at least up to a point Some human neuropathological studies suggest tangles may precede amyloid plaques Such studies may not have searched systematically for diffuse plaques or soluble Aβ oligomers in the brain. Human genetics proves that Aβ-elevating APP mutations lead to downstream alteration and aggregation of wild-type tau, whereas tau mutations do not lead to Aβ deposition and amyloid-related dementia A hypothesis that AD is fundamentally due to loss of presenilin function has been put forward AD-causing presenilin mutations may indeed act through partial loss of function of this protease, but these heterozygous mutations do not produce clinically detectable loss of presenilin function (e.g., Notch phenotypes), and organismal development and function are normal until the carriers develop typical AD symptoms in mid-life, heralded by elevated Aβ42/43 to Aβ40 ratios. Moreover, 99.9% of all AD patients have wild-type presenilins Numerous clinical trials of anti-amyloid agents have not met their pre-specified endpoints Several of these agents had inadequate preclinical data, poor brain penetration, little human biomarker change, and/or low therapeutic indexes (e.g., tramiprosate; R-flurbiprofen; semagacestat). Most such failed trials enrolled many patients in the late-mild and moderate stages of AD, whereas other trials conducted in very mild or mild AD produced suggestive evidence of clinical benefit. AD trials done prior to obligatory amyloid-PET imaging turned out to have up to ~25% of subjects that were amyloid-negative (i.e., did not have AD) New insights from AD genetics and APP homeostasis The fact that AD-causing mutations in APP and in presenilins 1 and 2 alter APP proteolytic processing in a way that elevates the relative levels of the Aβ42 or Aβ43 peptides has long been known (Scheuner et al, 1996; NB: Those mutations in APP that lie within the Aβ sequence increase the self-aggregation of the resultant peptides, not their production). A key mechanistic explanation was the discovery that the presenilin genes encode the active site of the intramembrane-cleaving γ-secretase enzyme (De Strooper et al, 1998; Wolfe et al, 1999). Subsequent studies have begun to illuminate how presenilin mediates intramembrane proteolysis (Qi-Takahara et al, 2005; Takami et al, 2009; Chavez-Gutierrez et al, 2012; Okochi et al, 2013; Fernandez et al, 2014): an initial endopeptidase cleavage of APP near the transmembrane/cytoplasmic interface of APP (the ε-cleavage) is followed by multiple carboxypeptidase cleavages that each sequentially removes 3 or 4 C-terminal amino acids (i.e., approximately one turn of the intramembrane helix) (Fig 2). This process yields two product lines that start with either the Aβ48/49 or the Aβ49/50 ε-cleavage. Although the precise molecular effects of different presenilin mutations differ somewhat, in all cases the mutations appear to decrease this C- to N-terminal cleavage "processivity" and thus increase the relative production of longer (more hydrophobic and self-aggregating) Aβ peptides. This elegant model provides a biochemical explanation for earlier work showing that pathogenic presenilin mutations often increase the Aβ42/Aβ40 ratio in humans. γ-Secretase reactions conducted directly in presenilin-mutant AD brain tissue showed that all presenilin mutations studied decreased this carboxypeptidase-like activity, and assays in a few "sporadic" AD brains suggested that a similar decrease in processivity might occur in some non-presenilin-mutant cases (Szaruga et al, 2015). Aβ42, Aβ43, and longer Aβ peptides are highly self-aggregating, whereas Aβ40 may actually be anti-amyloidogenic (Kim et al, 2007). Figure 2. Progressive cleavages of the APP transmembrane domain by the Presenilin/γ-secretase complex Download figure Download PowerPoint One group has emphasized that the aforementioned mechanism represents a loss of function of presenilin and have proposed that the neural phenotype of AD patients is fundamentally due to a loss of presenilin function, independent of effects on Aβ production (Shen & Kelleher, 2007; Xia et al, 2015). They have studied presenilin-1 mutations that generally lower Aβ and hardly raise relative Aβ42 levels, but this work may overlook an elevation of the Aβ43 and other longer species, which are highly amyloidogenic (Saito et al, 2011). Although AD-causing presenilin mutations can indeed be interpreted as partial loss of function from a genetics perspective, pinpointing the function of presenilin as an aspartyl endopeptidase allows one instead to speak in biochemical terms of a functional shift of the principal proteolytic cleavages to more C-terminal bonds in the substrate (Kretner et al, 2016). Humans with pathogenic presenilin mutations are heterozygotes and experience no loss of function of Notch cleavage; rather, they have accelerated Aβ42 and Aβ43 accumulation that long precedes their AD-typical memory syndrome. Most importantly, > 99% of all AD patients (including all other forms of familial disease) express wild-type presenilin, so loss of presenilin function cannot be a general mechanism of AD pathogenesis. The original formulation of the amyloid hypothesis was based in part on the discovery that the APP gene is on chromosome 21, implying that individuals with Down's syndrome develop typical Alzheimer neuropathology because they produce too much Aβ lifelong. This supposition has been substantiated by the identification of humans with different segmental microduplications of sub-regions of chromosome 21. Rare individuals with translocation Down's syndrome involving only the distal part of chromosome 21 telomeric to the APP gene have Down's features but do not get AD (Prasher et al, 1998). Conversely, those rare individuals who have the APP gene micro-duplicated but not the rest of the chromosome do not have Down's syndrome but get AD, typically in their mid-50s (Rovelet-Lecrux et al, 2006). These findings show conclusively that lifelong overexpression of wild-type APP causes AD. Even more remarkable has been the identification of an APP missense mutation (A673T) at the second amino acid of the Aβ region that results in a lifelong decrease in APP cleavage by β-secretase (Jonsson et al, 2012). Moreover, this benefit may be compounded, because the mutant Aβ peptide that is generated has altered aggregation properties (Benilova et al, 2014; Maloney et al, 2014; Zheng et al, 2015). A673T carriers have a lower risk of clinical AD and even of age-related cognitive decline without clinical AD (Jonsson et al, 2012), and they may not show plaque deposition at age 100 (Kero et al, 2013). The reduced amyloid deposition resulting from this AD-protective mutation strongly supports the amyloid hypothesis. Improved modeling of the amyloid hypothesis in rodent and cellular systems Concern has been expressed about the limitations of available rodent and cellular models of β-amyloid pathogenicity (Table 2). Early APP mouse models (e.g. Games et al, 1995; Hsiao et al, 1996) suffered from reliance on high transgene expression to drive plaque deposition and from a lack of tangle cytopathology and neuronal death. Crossing FAD-mutant APP mice with mutant MAPT (tau) transgenic (tg) mice succeeded in augmenting tau pathology and suggested that tangle-like changes occur downstream of Aβ accumulation, but this involved transgene overexpression and multiple AD mutations (Lewis et al, 2001). Recently, mice with gradual Aβ plaque accrual have been developed by the judicious use of selective knockin of human mutations into endogenous mouse APP without overexpression (Saito et al, 2014). Moreover, stem cell-derived human neurons cultured from skin biopsies of FAD subjects have been used to show first Aβ accumulation and then tau alteration in the absence of overexpression (Shi et al, 2012; Choi et al, 2014; Muratore et al, 2014; Moore et al, 2015) suggesting that the lack of tangle formation in early mouse models was related to the absence of human tau. This progress means we are now able to model a substantial part of the amyloid cascade in culture. In both cellular and mouse models, extensive data now suggest that the neurotoxicity of Aβ is in considerable part dependent on expression of human tau (Rapoport et al, 2002; Jin et al, 2011; Roberson et al, 2011). Table 2. Toward a more complete modeling of the pathogenesis of AD amyloid Year System Achievement Critique References 1995 APP transgenic mouse Plaque Pathology Overexpression, no downstream pathology Games et al (1995) 2000 MAPT mutant transgenic mouse Tangle Pathology Overexpression: no plaque pathology Lewis et al (2000) 2001 APP X MAPT transgenic mice Plaque and tangle pathology Overexpression of both transgenes: artificiality of two mutations Lewis et al (2001) 2012 Down's syndrome derived stem cell neurons Diffuse plaque pathology: evidence for pre-tangles Not full pathology Shi et al (2012) 2014 Complex APP mutation knockin into mouse genome Plaque pathology without overexpression Artificiality of multiple mutations: no downstream pathology Saito et al (2014) 2014 Overexpression of APP mutations in human neuronal lines in gel system Convincing plaque pathology and also tangle pathology Overexpression Choi et al (2014) 2015 APP and PSEN mutant stem cell lines Diffuse plaque pathology and tau pathology Moore et al (2015) Cell biology of new AD risk genes Although the importance of ApoE4 as the major risk factor for AD was discovered in 1993 (Corder et al, 1993), it is only since the advent of genomewide association studies and, more recently, exome and genome sequencing that other risk loci for late-onset disease have been discovered. Whereas the recently described loci are usually much weaker in effect (Lambert et al, 2013) or much rarer (Guerreiro et al, 2013; Jonsson et al, 2013) than ApoE4, they have helped delineate additional biological processes in AD pathogenesis. Three types of processes have emerged as especially important: cholesterol/sterol metabolism; inflammation and the brain's innate immune system; and endosomal vesicle recycling (Jones et al, 2010). Apolipoprotein E and other components of cholesterol/sterol metabolism A role for cholesterol in AD has long been suspected, based on the genetic implication of ApoE in the disease as well as the contrasting effects of cholesterol loading or depletion on amyloid pathology in APP tg mice (Refolo et al, 2000, 2001). Work in APP mice expressing different human ApoE alleles has shown that a major pathogenic influence of ApoE involves differential isoform effects on the clearance of Aβ (Castellano et al 2011: discussed below). The ABCA7 lipid transporter has also been identified as a genetic locus for the disease (Hollingworth et al, 2011), and loss-of-function mutations increase AD risk about threefold (Steinberg et al, 2015). ABCA7 is expressed in neurons, microglia, and peripheral macrophages, and it normally promotes the efflux of lipids from cells to apolipoproteins and also regulates phagocytosis. Crossing ABCA7 knockout mice to mutant hAPP mice caused a doubling of insoluble Aβ levels and amyloid plaques without changing APP processing, suggesting that like ApoE, ABCA7 is involved in Aβ clearance (Kim et al, 2013). However, the biochemical details through which both ApoE and ABCA7 influence the development of Aβ pathology need to be pinpointed. The innate immune system in Alzheimer's disease Neuropathologists have long suggested that the brain's innate immune system, including the microglial response to plaque formation, was an important factor in AD pathogenesis. For example, the early observation of multiple elements of the classical complement cascade in and around neuritic plaques (McGeer et al, 1989) was prescient. In the last few years, genetic variability in that system has emerged as a compelling determinant of AD risk, implicating many components of innate immunity and the complement cascade as risk factors in the disease (Jones et al, 2010). Three such risk genes have been investigated in some detail: Complement Receptor 1 (CR1; Lambert et al, 2009), CD33 (Bertram et al, 2008), and TREM2, and all three appear to be involved either directly or indirectly in the response of microglia to Aβ deposition. Blockade of CR1 inhibits microglial activation and potentiates microglial phagocytosis (Crehan et al, 2013). Inactivation of CD33 in primary microglia also potentiates microglial uptake of Aβ (Griciuc et al, 2013), and TREM2 is responsible for sustaining microglial phagocytosis of Aβ (Wang et al, 2015). Thus, all three genetically implicated microglial proteins may be involved in helping to maintain the AD microglial phenotype of phagocytosing Aβ deposits. Accordingly, these 3 genes undergo increased expression during plaque development (Griciuc et al 2013, Wang et al, 2015; Matarin et al, 2015) and CSF TREM2 levels go up as plaque load increases, suggesting it may be a useful biomarker (Suárez-Calvet et al, 2016). TREM2 is emerging as a key molecular determinant of the CNS response to Aβ accumulation (Forabosco et al, 2013; Zhang et al, 2013; Matarin et al, 2015). However, the biology of TREM2, a Type 1 single-transmembrane receptor which is principally but not exclusively expressed in microglia and undergoes ADAM/γ-secretase processing (Wunderlich et al, 2013; Kleinberger et al, 2014), is incompletely understood [reviewed in (Lue et al, 2015)]. The most studied mutation, R47H, may increase the risk of AD to the same extent that ApoE4 does although it is much rarer (Guerreiro et al, 2013; Jonsson et al, 2013). The upregulation of TREM2 in a subset of microglia in amyloid plaques of hAPP tg mice (e.g., Guerreiro et al, 2013) suggests that the known function of TREM2 in phagocytosis is compromised during plaque development. A current hypothesis is that R47H and other AD-associated TREM2 mutations confer loss of function in microglia. Deleting one TREM2 allele in hAPP tg mice significantly decreased the number of microglia associated with Aβ deposits (Ulrich et al, 2014). Conversely, TREM2 overexpression in hAPP tg mice decreased amyloid plaque burden, neuroinflammation, synapse loss, and spatial memory deficits (Jiang et al, 2014). And TREM2 mutations can alter its transport to the cell surface and shedding, associated with impaired phagocytic function (Kleinberger et al, 2014). The latter work has led to evidence that levels of the shed ectodomain in extracellular fluid and CSF are lower in AD cases associated with TREM2 mutations. Endosomal vesicle recycling in Alzheimer's disease The final set of recently identified loci for late-onset AD map to processes regulating endosomal vesicle recycling (Jones et al, 2010). This category includes SORL1, BIN1, and PICALM (Rogaeva et al, 2007; Lambert et al, 2013; Zhao et al, 2015). SORL1 had previously been shown to be directly involved in the processing of APP (Andersen et al, 2005), and work in human stem cell-derived neurons carrying the SORL1 risk haplotype confirmed this association (Young et al, 2015). Likewise, PICALM appears to be involved directly in endosomal APP processing (Kanatsu et al, 2014). In addition, PICALM has been implicated in the transport of brain Aβ across the blood–brain barrier: induced pluripotent stem cell (iPSC)-derived human endothelial cells carrying an AD-protective allele exhibited higher PICALM levels and enhanced Aβ clearance (Zhao et al, 2015). In summary, mechanistic studies linking several of the recently identified risk genes for late-onset (previously "sporadic") AD to aspects of Aβ homeostasis provide new support for the amyloid hypothesis as a driving factor in AD pathogenesis. They also suggest new avenues for therapeutic intervention, such as intervening in brain cholesterol metabolism and modulating the response of the innate immune system to amyloid deposition. Recent findings help resolve controversies about the role of Aβ Connecting plaques and tangles: Aβ can drive tau alteration The temporal sequence of the two canonical lesions Alois Alzheimer noted in his 1906 index case has been debated ever since. An elegant histopathological staging system created by Braak and Braak (1991) is now widely used to establish the severity of AD neuropathology. This scale principally described the progression of AD-type cytoskeletal changes, that is, neurofibrillary tangles and dystrophic neurites, in unrelated humans of increasing age (it could not yet include assays for accrual of oligomeric forms of Aβ). The detection of modest amounts of neurofibrillary change in limbic regions of young or middle-aged individuals dying of other causes does not imply that such individuals would necessarily have developed AD had they lived longer. Instead, human genetic and biomarker studies have provided the answer to the sequence of Aβ and tau accumulation in AD. Inherited mutations in APP and presenilin (i.e., in the substrate and the protease for Aβ generation) cause early-onset Aβ deposition (Lemere et al, 1996a,b; Bateman et al, 2012) followed by accumulation of tangles/neurites containing filaments of wild-type tau, so amyloid can clearly precede tangles in humans. In contrast, mutations in the tau gene lead to a form of frontotemporal dementia without subsequent accrual of Aβ. Thus, Aβ accumulation can lead to progressive tau deposition, but the converse has not been clearly demonstrated in humans. Laboratory studies support this sequence. Crossing hAPP tg mice with hTau tg mice significantly enhances tau deposition without changing Aβ deposition (Lewis et al, 2001). Crossing an APP tg mouse to a tau knockout mouse leads to substantially less behavioral deficits in the offspring than when tau is expressed (Roberson et al, 2011). Treating normal rat neurons in culture with soluble Aβ oligomers isolated from AD cortex causes neuritic dystrophy and AD-type tau hyperphosphorylation, but no dystrophy ensues if tau is first knocked down (Jin et al, 2011). Several similar studies suggest that Aβ—particularly soluble oligomers of Aβ42 (Shankar et al, 2008)—can trigger AD-type tau alterations, supporting the sequence that human genetics has indicated. The expression of human tau seems to be "permissive", enabling certain downstream neuronal consequences of progressive Aβ accrual to occur (Maruyama et al, 2013). How ApoE4 promotes AD: chronically decreased Aß clearance Humans expressing the ApoE4 protein develop more plaque and vascular β-amyloid deposits than those expressing only ApoE3 (Rebeck et al, 1993), and this has been confirmed in genetically engineered mice (Holtzman et al, 2000). A detailed quantitative study of Aβ homeostasis using in vivo microdialysis in hAPP × hApoE crossed mice has shown that Aβ clearance (but not Aβ production) is decreased by ApoE4 > E3 > E2, closely paralleling the degree of Aβ deposition in such mice (Castellano et al, 2011). The decrease in clearance of soluble Aβ was observed in young mice well before any amyloid deposition. The results strongly suggest that ApoE contributes to AD risk at least in part by differentially regulating sol

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Alzheimer's disease

2021-03-02

Philip Scheltens , Bart De Strooper , Miia Kivipelto +5 more

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Alzheimer's disease

2006-07-01

Kaj Blennow , Mony J. de Leon , Henrik Zetterberg

Alzheimer's disease

2016-02-25

Philip Scheltens , Kaj Blennow , Monique M.B. Breteler +4 more

Alzheimer's Disease

2010-01-27

Henry Querfurth , Frank M. LaFerla

This review of Alzheimer's disease assembles a variety of findings relevant to the mechanism of the disease and ties them together using the current understanding of the basis of the … This review of Alzheimer's disease assembles a variety of findings relevant to the mechanism of the disease and ties them together using the current understanding of the basis of the loss of cognition: the accumulation of misfolded proteins, which cause oxidative and inflammatory damage to the brain and, ultimately, synaptic dysfunction.

Lecanemab in Early Alzheimer’s Disease

2022-11-30

Christopher H. van Dyck , Chad J. Swanson , Paul Aisen +7 more

The accumulation of soluble and insoluble aggregated amyloid-beta (Aβ) may initiate or potentiate pathologic processes in Alzheimer's disease. Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to … The accumulation of soluble and insoluble aggregated amyloid-beta (Aβ) may initiate or potentiate pathologic processes in Alzheimer's disease. Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils, is being tested in persons with early Alzheimer's disease.

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Autophagy activators normalize aberrant Tau proteostasis and rescue synapses in human familial Alzheimer's disease iPSC-derived cortical organoids

2025-06-25

Sergio R. Labra , Jadon Compher , Akhil Prabhavalkar +7 more | bioRxiv (Cold Spring Harbor Laboratory)

Alzheimer's disease (AD) is the most common form of dementia worldwide. Despite extensive progress, the cellular and molecular mechanisms of AD remain incompletely understood, partially due to inadequate disease models. … Alzheimer's disease (AD) is the most common form of dementia worldwide. Despite extensive progress, the cellular and molecular mechanisms of AD remain incompletely understood, partially due to inadequate disease models. To illuminate the earliest changes in hereditary (familial) Alzheimer's disease, we developed an isogenic AD cerebrocortical organoid (CO) model. Our refined methodology produces COs containing excitatory and inhibitory neurons alongside glial cells, utilizing established isogenic wild-type and diseased human induced pluripotent stem cells (hiPSCs) carrying heterozygous familial AD mutations, namely PSEN1 ΔE9/WT, PSEN1M146V/WT, or APPswe/WT. Our CO model reveals time-progressive accumulation of amyloid beta (Aβ) species, loss of monomeric Tau, and accumulation of aggregated high-molecular-weight (HMW) phospho(p)-Tau. This is accompanied by neuronal hyperexcitability, as observed in early human AD cases on electroencephalography (EEG), and synapse loss. Single-cell RNA-sequencing analyses reveal significant differences in molecular abnormalities in excitatory vs. inhibitory neurons, helping explain AD clinical phenotypes. Finally, we show that chronic dosing with autophagy activators, including a novel CNS-penetrant mTOR inhibitor-independent drug candidate, normalizes pathologic accumulation of Aβ and HMW p-Tau, normalizes hyperexcitability, and rescues synaptic loss in COs. Collectively, our results demonstrate these COs are a useful human AD model suitable for assessing early features of familial AD etiology and for testing drug candidates that ameliorate or prevent molecular AD phenotypes.

Novel insights from comprehensive analysis: The role of cuproptosis and peripheral immune infiltration in Alzheimer’s disease

2025-06-25

Jing Wang , Zi-Wen Yu , Qi Liu +7 more | PLoS ONE

Background Cuproptosis is increasingly recognized as an essential factor in the pathological process of Alzheimer’s disease (AD). However, the specific role of cuproptosis-related genes in AD remains poorly understood. Methods … Background Cuproptosis is increasingly recognized as an essential factor in the pathological process of Alzheimer’s disease (AD). However, the specific role of cuproptosis-related genes in AD remains poorly understood. Methods Our first step was to obtain gene expression data from the GEO database and identify differentially expressed cuproptosis-associated genes (DECAGs) in AD. GO, KEGG, and GSEA analyses were then conducted on these genes. Subsequently, we attempted to classify AD patients by unsupervised clustering. Then, four machine-learning models were used to screen hub-genes from the DECAGs. We also explored the immune features of these genes and predicted target drugs. Molecular docking analysis was then performed on the predicted drugs and their corresponding hub-gene related proteins. Candidate markers were then validated by single-cell analysis and intracellular communication was investigated in a GEO scRNA-seq dataset. Lastly, we examined the expression levels of the hub-genes in peripheral blood cells using real-time quantitative PCR. Results 19 DECAGs were found in AD and the key biological processes and molecular functions associated with AD were further determined. Two subtypes of peripheral blood cells showed significant alternations in AD: Cluster1 and Cluster2. Five hub-genes including FDX1 , GLS , PDK1 , MAP2K1 , and SOD1 were then screened out from the machine-learning study. All of the five hub-genes were significantly correlated with various immunocytes. We discovered compounds targeting hub-gene related proteins and forecasted multiple strong hydrogen bonding interactions between the picked predicted drugs and the target proteins by molecular docking analysis. Subsequently, in the single-cell analysis of AD peripheral blood, all hub-genes except SOD1 were found to be up-regulated in B cells, NK cells, and CD4+ T cells, possibly acting on the MIF pathway. Finally, we discovered that the levels of PDK1 expression in AD patients were remarkably upregulated, while FDX1 and GLS were significantly decreased using qPCR. Conclusion This study examined changes in intercellular communication between immune cells in the peripheral blood and identified five novel feature genes associated with cuproptosis in AD patients. These results facilitated a deeper understanding of the molecular mechanisms of AD and suggested novel therapeutic targets.

Notoginsenoside <scp>R1</scp>, a Novel Natural <scp>PPARγ</scp> Agonist, Attenuates Cognitive Deficits in a Mouse Model of Diabetic Alzheimer's Disease Through Enhancing <scp>GLUT4</scp>‐Dependent Neuronal Glucose Uptake

2025-06-25

Zongyang Li , Yuan Zhang , Rui Su +7 more | Phytotherapy Research

ABSTRACT Our previous studies demonstrated the potential of notoginsenoside R1 (NGR1), a primary bioactive compound from Panax notoginseng , in alleviating diabetic encephalopathy in db/db mice and mitigating amyloid‐β (Aβ)‐induced … ABSTRACT Our previous studies demonstrated the potential of notoginsenoside R1 (NGR1), a primary bioactive compound from Panax notoginseng , in alleviating diabetic encephalopathy in db/db mice and mitigating amyloid‐β (Aβ)‐induced neuronal damage. This study aimed to investigate the positive effects of NGR1 against cognitive deficits in a diabetic Alzheimer's disease (AD) mouse model (APP/PS1x db/db mice). APP/PS1x db/db mice were intragastrically administrated with NGR1 (40 mg/kg/day) or co‐administrated with NGR1 and a selective PPARγ inhibitor GW9662 for 16 weeks. We identified NGR1 as a novel PPARγ agonist through molecular docking, surface plasmon resonance, and dual‐luciferase reporter assay. NGR1 treatment significantly promoted the membrane translocation of GLUT4 and enhanced 2‐deoxyglucose uptake in primary mouse hippocampal neurons. Furthermore, NGR1 treatment notably mitigated cognitive deficits in APP/PS1x db/db mice. This treatment correlated with reduced blood glucose levels, lowered blood HbA1c, and decreased serum insulin levels, coupled with enhanced glucose tolerance and insulin sensitivity. Additionally, NGR1 treatment ameliorated Aβ burden, suppressed microglia‐induced neuroinflammation, and notably increased cerebral glucose uptake, as demonstrated by 18 F‐FDG PET scans. NGR1 treatment could upregulate PPARγ and GLUT4 expression and increase phosphorylation of Akt at Ser473 while decreasing phosphorylation of IRS‐1 at Ser616 in the hippocampus of APP/PS1x db/db mice. Crucially, the protective effects of NGR1 were abolished by co‐administration with GW9662. NGR1 demonstrated efficacy in enhancing neuronal glucose uptake through the activation of the PPARγ/Akt/GLUT4 signaling pathways in APP/PS1x db/db mice, positioning it as a promising candidate for diabetic AD treatment.

PGRN Counteracts the Associations of Abnormal Tau Proteins with Neurodegeneration and Cognitive Decline in Non-demented Adults: A Longitudinal Study

2025-06-25

Yifan Sun , Yanbing Liu , Chen‐Chen Tan +2 more | Molecular Neurobiology

Effects of regional white matter hyperintensities and β-amyloid on domain-specific cognition and progression to dementia

2025-06-24

Cameron Mavericks Choo , Chin Hong Tan | Brain and Cognition

White matter hyperintensities (WMHs) and cerebral β-amyloid (Aβ) have been characterized as clinically significant biomarkers associated with greater cognitive decline and incidence of Alzheimer's Disease (AD) dementia. However, it remains … White matter hyperintensities (WMHs) and cerebral β-amyloid (Aβ) have been characterized as clinically significant biomarkers associated with greater cognitive decline and incidence of Alzheimer's Disease (AD) dementia. However, it remains unclear how their regional manifestations co-contribute to domain-specific cognition and dementia onset. We investigated 200 cognitively normal (CN) and 523 individuals with mild cognitive impairment (MCI). We first quantified regional WMHs and Aβ accumulation in the four cerebral lobes. Next, we evaluated the effects of both WMHs and Aβ in each lobe on memory, executive function (EF), language, and visuospatial function. We used Cox proportional hazard models to determine the contributions of both regional WMHs and Aβ to dementia progression. In CN individuals, greater WMHs in parietal and temporal regions were associated with poorer EF beyond Aβ. In MCI individuals, greater Aβ burden in all lobes were associated with poorer memory, EF, and language abilities beyond WMHs. Lastly, both greater occipital WMHs and Aβ predicted progression to dementia. Temporo-parietal WMHs may drive early decline in EF beyond regional Aβ, while occipital WMHs play a critical role in disease progression to AD dementia beyond regional Aβ, highlighting the complex interplay of regional WMHs and Aβ on domain-specific cognitive and clinical function.

Co-Morbid Disease as Risk Factors Associated with Alzheimer’s Disease- An Overview

2025-06-24

Akhilesh K. Tyagi , Nikhila Shekhar , Sakshi Tyagi | Current Behavioral Neuroscience Reports

Microgravity-Assisted Exploration of the Conformational Space of Amyloid β Affected by Tottori-Type Familial Mutation D7N

2025-06-24

Maho Yagi‐Utsumi , Saeko Yanaka , Raymond N. Burton‐Smith +7 more | ACS Chemical Neuroscience

The amyloid β (Aβ) Tottori variant (D7N) exhibits unique aggregation behaviors and altered fibril formation, posing challenges for structural characterization. To overcome this, the microgravity environment on the International Space … The amyloid β (Aβ) Tottori variant (D7N) exhibits unique aggregation behaviors and altered fibril formation, posing challenges for structural characterization. To overcome this, the microgravity environment on the International Space Station was employed to study Tottori-type Aβ40 fibril formation and structure. Under Earth gravity, Tottori-type Aβ40 primarily formed nonfibrillar aggregates, hindering detailed structural analysis. In contrast, microgravity significantly enhanced fibril formation and minimized amorphous aggregates. Cryo-electron microscopy revealed two structurally distinct fibril types, each comprising different protomer conformations. In both types, the N-terminal segment was disordered and nor resolved in the density maps. The D7N mutation disrupts the protection of the core by the N-terminal segment often observed in wild-type Aβ40 fibrils, enhancing the hydrophobicity-mediated aggregation propensity. However, microgravity suppressed kinetic traps and facilitated high-quality fibril formation suitable for structural studies that can explore the free energy landscape of Aβ fibril formation. These findings demonstrate the utility of microgravity for studying familial Aβ variants and potentially accelerate our understanding of Aβ aggregation mechanisms in Alzheimer's disease.

Optimizing Alzheimer's diagnosis and precision medicine: A narrative review unlocking the potential of multiomics markers

2025-06-24

Jérôme Braudeau , Benoît Souchet , Emmanuel Streel | NeuroMarkers.

Alzheimer’s Is Not a Single Disease

2025-06-24

Donald F. Weaver | ACS Chemical Neuroscience

Neuroprotective Mechanisms of Porcine Brain Enzyme Hydrolysate in Memory Impairment: Multi-Target Strategy Against Amyloid-β-Induced Neurotoxicity

2025-06-24

Sun Myung Yoon , Ye-Won Lee , Min Ju Kim +3 more | International Journal of Molecular Sciences

This study investigated the potential neuroprotective mechanisms of porcine brain enzyme hydrolysate (PBEH) against Alzheimer’s disease pathology using differentiated SH-SY5Y cells. Differentiated neuronal cells were treated with 40 μM amyloid-β(1-42; … This study investigated the potential neuroprotective mechanisms of porcine brain enzyme hydrolysate (PBEH) against Alzheimer’s disease pathology using differentiated SH-SY5Y cells. Differentiated neuronal cells were treated with 40 μM amyloid-β(1-42; Aβ) to induce neurotoxicity, followed by PBEH treatment (12.5–400 μg/mL), Com-A (peptide-based neuroprotective supplement; 200 μg/mL) treatment, and Com-B (herbal extract known for improving memory function; 100 μg/mL) treatment. Key assessments included cell viability, Aβ aggregation in adding 10 μM Aβ, amyloidogenic proteins (APP, BACE), synaptic markers (BDNF, ERK), apoptotic markers (BAX/BCL-2, caspase-3), oxidative stress (reactive oxygen species (ROS)), cholinergic function (ChAT, AChE), MAPK signaling (JNK, p38), and neuroinflammation (IL-1β). PBEH contained high concentrations of amino acids, including L-lysine (32.3 mg/g), L-leucine (42.4 mg/g), L-phenylalanine (30.0 mg/g) and the PSIS peptide (86.9 μg/g). Treatment up to 400 μg/mL showed no cytotoxicity and had cognitive protection effects up to 152% under Aβ stress (p < 0.05). PBEH significantly attenuated Aβ aggregation, decreased APP (28%) and BACE (51%) expression, enhanced synaptic function through increased BDNF, and restored ERK phosphorylation (p < 0.05). Anti-apoptotic effects included a 76% reduction in the BAX/BCL-2 ratio, a 47% decrease in caspase-3, and a 56% reduction in ROS levels. Cholinergic function showed restoration via increased ChAT activity (p < 0.01) and decreased AChE activity (p < 0.05). PBEH reduced IL-1β levels by 70% and suppressed JNK/p38 phosphorylation (p < 0.05). While Com-A enhanced BDNF and Com-B showed anti-inflammatory effects, PBEH demonstrated activity across multiple pathway markers. In conclusion, these findings suggest that PBEH may enable neuronal preservation through multi-pathway modulation, establishing foundational evidence for further mechanistic investigation in cognitive enhancement applications.

Interplay Between Aging and Tau Pathology in Alzheimer’s Disease: Mechanisms and Translational Perspectives

2025-06-24

Mohammed Alrouji , Mohammed S. Alshammari , Tasqeeruddin Syed +1 more | Antioxidants

Aging is a key risk factor for neurodegenerative disorders and is associated with widespread systemic and brain-specific changes. Alzheimer’s disease (AD), a progressive and irreversible brain disorder, primarily affects older … Aging is a key risk factor for neurodegenerative disorders and is associated with widespread systemic and brain-specific changes. Alzheimer’s disease (AD), a progressive and irreversible brain disorder, primarily affects older adults and leads to a gradual decline in cognitive function. The underlying disease mechanisms often begin years before clinical symptoms appear, limiting the effectiveness of current treatments. Several factors linked to aging—including inflammation, oxidative stress, impaired metabolism, and protein aggregation—contribute to the onset and progression of AD. A central feature of AD is the abnormal accumulation of amyloid beta (Aβ) and tau, a microtubule-associated protein, driven by post-translational modifications such as acetylation and hyperphosphorylation. These modifications lead to structural changes in tau, promoting the formation of neurofibrillary tangles (NFTs), which are more closely associated with cognitive decline than Aβ plaques. Interestingly, tau accumulation and the resulting cognitive impairments are often observed in aged individuals without Aβ deposition, highlighting tauopathy as a distinct contributor to age-related cognitive decline. This review focuses on new developments in therapeutic approaches that target oxidative stress, protein aggregation, and neuroinflammation, and our current understanding of the molecular pathways relating aging and tau pathology in AD.

Identification of Associations Between Peripheral Blood Gene Expression and Cerebrospinal Fluid Biomarkers in Alzheimer's Disease Using an Improved Joint Multi-Task Sparse Canonical Correlation Analysis Algorithm

2025-06-23

Qianqian Wu , Zhihui Ma , Feng Wang | Applied Biochemistry and Biotechnology

Unveiling the therapeutic potential of natural products in Alzheimer’s disease: insights from in vitro, in vivo, and clinical studies

2025-06-23

Nahida Aktary , Young Jin Jeong , Sang-Soo Oh +7 more | Frontiers in Pharmacology

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder described as progressive cognitive decline and neuronal dysfunction, affecting millions globally. While current pharmacological treatments provide symptomatic relief and modestly slow disease … Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder described as progressive cognitive decline and neuronal dysfunction, affecting millions globally. While current pharmacological treatments provide symptomatic relief and modestly slow disease progression, they fail to address the underlying pathophysiology and are often accompanied by severe adverse effects. This underscores the urgent need for innovative, multi-target therapeutic strategies that can effectively step in AD’s complex pathogenesis. Emerging evidence highlights the therapeutic potential of natural products, particularly herbal medicines, as versatile modulators of key pathogenic processes in AD. These compounds exert neuroprotective effects by mitigating oxidative stress, suppressing neuroinflammation, inhibiting tau hyperphosphorylation, and reducing amyloid-beta aggregation. Additionally, they strengthen synaptic plasticity and stabilize mitochondrial function, offering a holistic approach to disease control. This comprehensive review synthesizes findings from network pharmacology, in vitro and in vivo studies, and clinical trials to evaluate the role of natural products in AD treatment. Advances in bioinformatics and systems biology facilitate the mapping of intricate protein-protein interactions, the identification of potential biomarkers, and the clarification of molecular mechanisms underlying AD progression. Integrating phytochemicals with conventional AD medications may improve therapeutic efficacy through synergistic mechanisms; however, pharmacokinetic interactions and safety considerations must be rigorously assessed. Notably, clinical trials investigating compounds such as curcumin, resveratrol, and ginsenosides suggest promising adjunctive benefits when incorporated into established treatment regimens. Furthermore, the convergence of herbal therapeutics with modern pharmacology presents an avenue for customized and integrative AD management. This review also emphasizes advancements in experimental models, including brain organoids and transgenic animals, which serve as crucial platforms for mechanistic studies and therapeutic validation. Ongoing trials on plant-derived compounds continue to pave the way for translational applications, reinforcing the viability of natural product-based interventions. By advocating a multidisciplinary framework that merges traditional medicine, modern pharmacology, and precision medicine, this work contributes to reshaping the AD landscape of therapy. It provides a roadmap for future research, fostering novel treatment paradigms that prioritize efficacy, safety, and sustainability in combating this disastrous disorder.

New Frontier, New Challenges—Recognizing and Managing Adverse Effects of Antiamyloid Therapies

2025-06-23

Megan A. Rech , Neelum T. Aggarwal , Ula Hwang | JAMA Internal Medicine

This clinical insight discusses the diagnosis and management of adverse effects of antiamyloid therapies and what medications require consideration or avoidance. This clinical insight discusses the diagnosis and management of adverse effects of antiamyloid therapies and what medications require consideration or avoidance.

Expression and function of β-site amyloid precursor protein cleaving enzyme 2 in vascular endothelium

2025-06-23

Livius V. d’Uscio , Tetiana Kovalenko , Tongrong He +3 more | AJP Heart and Circulatory Physiology

The physiological function of β-site amyloid precursor protein-cleaving enzyme 2 (BACE2) in vascular endothelium of systemic arteries is unknown. In the present study we generated conditional tamoxifen-inducible endothelial BACE2 deficient … The physiological function of β-site amyloid precursor protein-cleaving enzyme 2 (BACE2) in vascular endothelium of systemic arteries is unknown. In the present study we generated conditional tamoxifen-inducible endothelial BACE2 deficient mice (eBACE2-/- mice). Electron-microscopic and western blot analyses revealed that BACE2 protein is mainly present in endothelial cells of aorta. Genetic deletion of BACE2 in endothelial cells significantly impaired endothelium-dependent relaxations to Ca2+-ionophore A23187 in eBACE2-/- aortas as compared to tamoxifen treated control mice irrespective of sex. Blockade of nitric oxide synthase (NOS) with Nω-nitro-L-arginine methyl ester abolished relaxations to A23187. In contrast, endothelium-independent relaxations to nitric oxide donor diethylamine-NONOate were unchanged. Expression of endothelial NOS protein and levels of cyclic nucleotides were also unaffected in eBACE2-/- mice. Further analysis of the mechanisms underlying impaired endothelial function demonstrated that treatment with thromboxane A2 receptor antagonist SQ29548 ameliorated relaxations to A23187 in the aorta of male and female eBACE2-/- mice. Furthermore, mRNA and protein expressions of cyclooxygenase-2 as well as production of thromboxane A2 and prostaglandin F2α were significantly increased in the aorta of eBACE2-/- mice. In contrast, production of 6-keto prostaglandin F1α and prostaglandin E2 were not affected. In addition, ex-vivo treatment of wild-type aortas with proinflammatory cytokines decreased protein expression of BACE2. The results of our study suggest that increased production of vasoconstrictor prostanoids are responsible for impairment of endothelium-dependent relaxations to A23187 in the aorta of eBACE2-/- mice. We report previously unrecognized role of BACE2 in control of endothelial arachidonic acid metabolism and vasomotor function.

Editorial: A comprehensive look at biomarkers in neurodegenerative diseases: from early diagnosis to treatment response assessment

2025-06-23

Riccardo Pascuzzo , Fulvia Palesi , Yi-Min Wan +1 more | Frontiers in Aging Neuroscience

Role of Oxidative Stress and Neuroinflammation in the Etiology of Alzheimer’s Disease: Therapeutic Options

2025-06-23

Marta Weinstock | Antioxidants

Cognitive impairment in subjects with Alzheimer’s disease correlates well with the loss of synaptic plasticity. This results from mitochondrial dysfunction and production of reactive oxygen species, which damage nerve terminals … Cognitive impairment in subjects with Alzheimer’s disease correlates well with the loss of synaptic plasticity. This results from mitochondrial dysfunction and production of reactive oxygen species, which damage nerve terminals causing them to release ATP and adenosine. These purines activate receptors on microglia resulting in a change in morphology and release proinflammatory cytokines that exacerbate neuronal damage. The review describes retrospective studies with naturally occurring antioxidants, vitamin E, resveratrol, Ginkgo biloba and others that suggested they reduce the incidence of Alzheimer’s disease. They have antioxidant activity in cellular systems and rodent models, but most of them failed in clinical trials, probably because they were not absorbed after oral administration or, like anti-inflammatory drugs, were not given at the right time or for long enough to detect an effect on disease progression. Ladostigil is an aminoindan derivative that is well absorbed after oral administration. It has antioxidant effects in cells and prevents cytokine release from activated microglia. In a phase 2 trial in subjects with mild cognitive impairment, ladostigil significantly reduced number of converters to Alzheimer’s disease in ApoE4-ve subjects and delayed the decline in whole brain and hippocampal volumes without causing adverse effects related to drug intake.

Management of Alzheimer's Disease With Nanotechnological Interventions and Novel Therapeutics

2025-06-23

Mohd Shahrukh , Shadaan Ahmad , Mohammed Zaafar +2 more | Drug Development Research

Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by cognitive deterioration, β-amyloid plaque buildup, intracellular tangles, and significant neuronal loss. The increasing prevalence of AD, along with its substantial … Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by cognitive deterioration, β-amyloid plaque buildup, intracellular tangles, and significant neuronal loss. The increasing prevalence of AD, along with its substantial economic burden, underscores the urgent need for effective therapeutic strategies in the near future. The challenge is early diagnosis and management, hindered by the lack of reliable biomarkers. Currently, there is no definitive cure for AD. Attaining improved therapeutic outcomes necessitates delivering optimal drug concentrations to the central nervous system (CNS) by effectively penetrating the blood-brain barrier (BBB). Recently, nanotechnology has emerged as a promising approach to address this challenge, enhancing brain-targeted drug delivery while highlighting recent advancements and future potential. Additionally, novel targeted therapies such as genetic therapeutics, stem cell therapy, and immunotherapy approaches overcome AD-based challenges, enhance treatment efficacy, and improve patient compliance. This review highlights recent advancements in the treatment of AD, focusing on nanotechnology-based drug delivery systems, and also explores genetic therapeutics, stem cell therapy, and immunotherapy approaches. Overall, the review provides a comprehensive overview of these therapeutic approaches, shedding light on the evolving landscape of AD treatment and the challenges that lie ahead.

Amyloid-β protein precursor fragments in urine: Potential biomarkers for the early detection of mild cognitive impairment and dementia

2025-06-23

Jingyu Zhu , Xiao Xiao , Xiaotong Chen +7 more | Journal of Alzheimer s Disease

BackgroundCurrent diagnostic methods have limitations in early prediction of dementia.ObjectiveDevelop an early screening tool to identify persons at high risk of dementia for early intervention.MethodsWe examined amyloid-β protein precursor (AβPP) … BackgroundCurrent diagnostic methods have limitations in early prediction of dementia.ObjectiveDevelop an early screening tool to identify persons at high risk of dementia for early intervention.MethodsWe examined amyloid-β protein precursor (AβPP) and its fragments in urine from cognitively normal controls (CNs) and patients with mild cognitive impairment (MCI) or Alzheimer's disease (AD)-dementia using western blotting with different antibodies and developed a colloidal gold lateral flow-based qualitative strip.ResultsCompared with CNs, the amounts of various AβPP fragments with molecular weights of approximately 14, 28, 56, and 68 kDa in patients were greater. We therefore used the strip to detect urine Aβ-containing AβPP fragments and evaluated its potential in multiple aged cohorts from 11 cities in Jiangsu Province, China (n = 4418); Sichuan Provincial People's Hospital (Chengdu, China; n = 408); and the Australian Imaging, Biomarker and Lifestyle Study (AIBL; n = 367). Unitizing Aβ-binding phagocytosis-promoting peptides, the strips showed increasing positivity (9.5-16.9%) with ageing in the Jiangsu cohort and good clinical performance in the Chengdu cohort (κ = 0.704). Significant differences between CNs and patients were found in the AIBL cohort with negative Aβ-PET, those with the slope of Aβ-PET change <1 centiloid per year, those under 75 years of age, or those with a body mass index of 25-30.ConclusionsOur data indicate the high potential of urine AβPP fragments as biomarkers for MCI and dementia at an early stage and warrant further longitudinal studies.

α-klotho as a biomarker of amyloid β levels in the cerebrospinal fluid

2025-06-23

Jacob Raber , Alexandra Pederson , Emily Bunnell +6 more | Frontiers in Aging Neuroscience

Introduction CSF α -klotho levels might affect Aβ40, Aβ42, and the Aβ42/40 ratio in the cerebrospinal fluid (CSF). Methods CSF α -klotho was assayed in ovariectomized rhesus macaques (NHPs) maintained … Introduction CSF α -klotho levels might affect Aβ40, Aβ42, and the Aβ42/40 ratio in the cerebrospinal fluid (CSF). Methods CSF α -klotho was assayed in ovariectomized rhesus macaques (NHPs) maintained on a Western-style diet (WSD) to assess the effect of estrogen hormone therapy (HT). CSF and serum α -klotho was also analyzed in females and males of different ages and whether it was associated with Aβ42, Aβ40, or the Aβ42/40 ratio. Furthermore, CSF and serum α -klotho were analyzed in women and men with dementia and controls and whether they were associated with CSF Aβ levels. Results HT was associated with increased CSF α -klotho levels. Furthermore, α -klotho and Aβ levels were correlated in a species- and cognitive health-dependent fashion. Higher CSF and serum levels of α -klotho were seen in controls than in patients with dementia. Discussion Understanding the species differences in the beneficial effects of α -klotho on CSF Aβ physiology should open new avenues for treating AD.

A Pilot Study on Blood Concentration of β-Amyloid (40 and 42) and Phospho-Tau 181 in Horses

2025-06-23

Valentina Gazzano , Maria Claudia Curadi , Simona Capsoni +4 more | Veterinary Sciences

In humans, aging is often accompanied by cognitive decline, as seen in Alzheimer’s disease. In contrast, the aging process in horses remains poorly characterized. This study aims to explore the … In humans, aging is often accompanied by cognitive decline, as seen in Alzheimer’s disease. In contrast, the aging process in horses remains poorly characterized. This study aims to explore the presence of blood-based biomarkers associated with cognitive degeneration in this species. Twenty-three Arabian horses were enrolled, and 5 mL of blood was collected from each to measure serum levels of β-amyloid peptides (Aβ40 and Aβ42) and phosphorylated tau protein (pTau181), both considered reliable indicators of cognitive impairment in other species. Aβ42 was undetectable in all samples, while pTau181 ranged from 5.38 to 54.42 pg/mL and Aβ40 from 67.4 to 743.9 pg/mL. Statistical analysis of the data, performed with the non-parametric Spearman test, did not reveal any correlation between age and the concentrations of Aβ40 and pTau. The pTau/Aβ40 ratio also did not appear to be correlated with the age of the subjects. Interestingly, none of the horses exhibited behavioral changes or clinical signs suggestive of cognitive dysfunction. This absence of symptoms may be related to the undetectable levels of Aβ42, the isoform considered crucial in initiating tau phosphorylation and subsequent neurodegeneration, despite possibly being present at concentrations higher than those typically found in healthy humans.

3-Hydroxyquinolin-2-Ones Act as Dual Inhibitors of Ferroptosis and Monoamine Oxidase B: Reducing Alzheimer’s Disease-Related Amyloid Precursor Protein and Hyperphosphorylated Tau In Vivo

2025-06-21

Yangjing Lv , Xiaoxin Song , Jiayan He +6 more | Journal of Medicinal Chemistry

The challenges in the current treatment landscape for Alzheimer's disease (AD) underscore the urgent need for novel therapeutic strategies targeting multiple pathological pathways. Recent studies have implicated iron in ROS-dependent … The challenges in the current treatment landscape for Alzheimer's disease (AD) underscore the urgent need for novel therapeutic strategies targeting multiple pathological pathways. Recent studies have implicated iron in ROS-dependent neuronal injury through ferroptosis. Additionally, overexpression of monoamine oxidase B (MAO-B) induces oxidative stress and decreases cognitive function. In this study, we presented the novel dual inhibitors of ferroptosis and MAO-B for AD management, aiming to address both the symptomatic and neurodegenerative aspects of this disease. Compound 21d emerged as a promising candidate, exhibiting potent and selective MAO-B inhibitory activity (IC50 = 87.47 nM, SI > 229), as well as excellent antiferroptosis activity through modulation of the iron metabolic pathway and GSH-GPX4 axis in vitro. Importantly, 21d normalized cognitive and memory impairments in a 3×Tg (APP/Tau/Ps1) AD mouse model and reduced levels of AD-related proteins, including amyloid precursor protein and phosphorylated Tau protein, in the brains of AD mice.

Advance and Prospect of Positron Emission Tomography in Alzheimer’s disease research

2025-06-21

Yulin Wang , Wanchen Liao , Lei Wang +5 more | Molecular Psychiatry

Dual Aβ/tau epitope vaccines: a poorly explored strategy for Alzheimer's disease immunotherapy

2025-06-21

Karen León‐Arcia , Gabriela Pérez-Leal , Heidi Quintero-Álvarez +4 more | Vaccine

Physics of Protein Aggregation in Normal and Accelerated Brain Aging

2025-06-20

Alberto J. Espay , Andrea Sturchio , Alberto Imarisio +7 more | BioEssays

ABSTRACT Protein aggregation is a normal response to age‐related exposures. According to the thermodynamic hypothesis of protein folding, soluble proteins precipitate into amyloids (pathology) under supersaturated conditions through a process … ABSTRACT Protein aggregation is a normal response to age‐related exposures. According to the thermodynamic hypothesis of protein folding, soluble proteins precipitate into amyloids (pathology) under supersaturated conditions through a process similar to crystallization. This soluble‐to‐insoluble phase transition occurs via nucleation and may be catalyzed by ectopic surfaces such as lipid nanoparticles, microbes, or chemical pollutants. The increasing prevalence of these exposures with age correlates with the rising incidence of pathology over the lifespan. However, the formation of amyloid fibrils does not inherently cause neurodegeneration. Neurodegeneration emerges when the levels of functional monomeric proteins, from which amyloids form, fall below a critical threshold. The preservation of monomeric proteins may explain neurological resilience, regardless of the extent of amyloid deposition. This biophysical framework challenges the traditional clinicopathological view that considers amyloids intrinsically toxic, despite the absence of a known mechanism of toxicity. Instead, it suggests that chronic exposures driving persistent nucleation consume monomeric proteins as they aggregate. In normal aging, replacement matches loss; in accelerated aging, it does not. A biophysical approach to neurodegenerative diseases has important therapeutic implications, refocusing treatment strategies from removing pathology to restoring monomeric protein homeostasis above the threshold needed to sustain normal brain function.

Comparison of two main fragmentation methods of amyloid beta fibrils for establishing an Alzheimer disease model in cell culture

2025-06-20

Elham Bahador Zırh , Hare Yazgı , Hilal Akyel +2 more | Acta Medica

Aim: Amyloid beta fibrils have been shown to play a role in plaque formation and aggregation in Alzheimer’s disease. Obtaining these fibrils using two main methods and applying them to … Aim: Amyloid beta fibrils have been shown to play a role in plaque formation and aggregation in Alzheimer’s disease. Obtaining these fibrils using two main methods and applying them to Alzheimer’s modelling is crucial in understanding the pathology of the disease at the molecular level and identify in therapeutic targets. The aim of our study is to determine the optimum sonication parameters using probe and ultrasonic bath sonication laboratory methods and to demonstrate Alzheimer’s disease modelling at the cellular level. Methods: Lyophilized human peptide amyloid beta1-42 fibrils (fAβ1-42) were subjected to probe sonication for 1 minute with 1, 3 and 5 second on/off pulse applications at varying ambient temperatures (room temperature, ice and ice surrounded by dry ice [ISDI]) for 20, 40 and 60 cycles, respectively. Then, ultrasonic bath sonication was performed in 10 °C water for 1 hour. The length of the fragmented fibrils was quantified by transmission electron microscopy (TEM). fAβ1-42 at different concentrations was applied to SH-SY5Y cell line. The non-toxic dose and time of fAβ1-42 application were analysed using the WST-1 assay. Intracellular and extracellular fibrils were visualized with immunofluorescence (IF) labelling. Results: Although, fragmentation was observed under all conditions, it was observed that fibrillar lengths decreased as the on/off pulse times increased, regardless of the number of cycles with ice and dry ice. Additionally, decreasing the temperature increased fibrillar fragmentation. Conclusion: We anticipate that our study will contribute to the literature by developing an effective and economical sonication method for fibrillar fragmentation with two main laboratory methods and obtaining fAβ1-42 that can be used in cells at optimum concentration.

The Role of S6K1 in Aging and Alzheimer’s Disease: Mechanistic Insights and Therapeutic Potential

2025-06-20

Salvatore Oddo , Marika Lanza , Giovanna Casili +1 more | International Journal of Molecular Sciences

Aging is the greatest risk factor for Alzheimer’s disease (AD), but the mechanisms connecting the two remain unclear. The mammalian target of rapamycin (mTOR) pathway, particularly its downstream effector S6 … Aging is the greatest risk factor for Alzheimer’s disease (AD), but the mechanisms connecting the two remain unclear. The mammalian target of rapamycin (mTOR) pathway, particularly its downstream effector S6 kinase 1 (S6K1), has emerged as a key regulator of aging and neurodegeneration. S6K1 controls translation, autophagy, and mitochondrial function—processes disrupted in both aging and AD. This review examines how S6K1 influences mitochondrial metabolism, autophagy, and metabolic dysfunction in aging. We also discuss its role in the nervous system, including effects on synaptic plasticity, memory, glial activation, and neuroinflammation. In AD, S6K1 contributes to amyloid and tau pathology by regulating translation of BACE1 and tau, and its hyperactivation is linked to synaptic deficits and cognitive decline. We further explore therapeutic strategies targeting S6K1, which have shown benefits for lifespan extension and neuroprotection in preclinical models. Finally, we consider the emerging link between S6K1 and necroptosis, a form of programmed cell death implicated in AD-related neuronal loss. Together, these findings highlight S6K1 as a promising target for interventions aimed at slowing aging and mitigating AD pathogenesis.

The Potential Regulators of Amyloidogenic Pathway of APP Processing in Alzheimer’s Disease

2025-06-20

Daria Krawczuk , Agnieszka Kulczyńska-Przybik , Barbara Mroczko | Biomedicines

The amyloidogenic processing of amyloid precursor protein (APP) plays a pivotal role in the pathogenesis of Alzheimer’s disease (AD), primarily through the generation of amyloid-beta (Aβ) peptides, which aggregate to … The amyloidogenic processing of amyloid precursor protein (APP) plays a pivotal role in the pathogenesis of Alzheimer’s disease (AD), primarily through the generation of amyloid-beta (Aβ) peptides, which aggregate to form toxic plaques in the brain. The regulation of amyloidogenic APP processing is a complex interplay of enzymes, proteins, and signaling pathways, all of which contribute to the development and progression of Alzheimer’s disease. Understanding the intricate mechanisms and molecular players involved in APP processing substantially enhances our knowledge of Alzheimer’s disease pathology and holds promise for the development of biomarkers of ongoing pathology at the earliest stages of Alzheimer’s disease. In this review, we aimed to investigate selected factors that regulate the amyloidogenic pathway of APP processing.

The Role of Astrocytes in Synaptic Dysfunction and Memory Deficits in Alzheimer’s Disease

2025-06-20

Cristina A. Muñoz de León-López , Irene Navarro‐Lobato , Zafar U. Khan | Biomolecules

Astrocytes are the most abundant glial cells in the brain. They play critical roles in synapse formation and function, neurotransmitter release and uptake, the production of trophic factors, and energy … Astrocytes are the most abundant glial cells in the brain. They play critical roles in synapse formation and function, neurotransmitter release and uptake, the production of trophic factors, and energy supply for neuronal survival. In addition to producing proteases for amyloid-β degradation, astrocytes express various receptors, transporters, gliotransmitters, and other molecules that enable them to sense and respond to external signals. They are also implicated in amyloid-β clearance. In Alzheimer’s disease, excessive accumulation of amyloid-β induces the polarization of astrocytes into the A1 phenotype, promoting the release of inflammatory cytokines and mitochondrial reactive oxygen species, leading to alterations in astrocytic functions. Under such conditions, gliotransmitter release, glutamate neurotransmission, AMPA receptor trafficking, and both Hebbian and non-Hebbian forms of synaptic plasticity—biological activities essential for synaptic functions—are compromised. Moreover, astrocytes are essential for learning, memory, and synaptic plasticity, and alterations in their function are associated with memory deficits in Alzheimer’s disease. This review provides an overview of the current understanding of the defects in astrocytes that lead to altered synaptic functions, neuronal structural plasticity, and memory deficits in Alzheimer’s disease.

Relationship Between Amyloid-beta Deposition and Tau Deposition in Alzheimer's Disease

2025-06-20

Siying Li | Theoretical and Natural Science

So far, the primary culprits in the onset of Alzheimer's disease are the deposits of amyloid- (A) proteins and the formation of tau protein knots. These markers are crucial for … So far, the primary culprits in the onset of Alzheimer's disease are the deposits of amyloid- (A) proteins and the formation of tau protein knots. These markers are crucial for a conclusive pathological diagnosis. Despite the significance of both amyloid- deposits and tau protein knots, the nature of their interaction remains largely unexplained, and the scientific inquiries into this relationship yield a patchy and inconclusive body of research. In this paper, we find out A plaques accelerate neurotic plaque tau aggregation and propagation and apply fluorescent biotechnique to detect and measure A oligomers in normal and tau seed condition. The findings indicate that upon introducing varied concentrations of A aggregates into culture mediums devoid of lipofectamine, both A filaments and newly synthesized A enhance tau nucleation in correlation with their concentration. Moreover, A oligomers exhibit a more pronounced stimulatory effect, strongly suggesting an interaction between A and tau.

Alzheimer's Disease and Adult Hippocampal Neurogenesis: Tracking A and Immature Neuron Markers

2025-06-20

Zhengyang Xu | Theoretical and Natural Science

From the work of Moreno-Jimenez et al., it is known that the generation of new neurons dramatically declines in patients with Alzheimers disease compared with mentally healthy individuals, marked by … From the work of Moreno-Jimenez et al., it is known that the generation of new neurons dramatically declines in patients with Alzheimers disease compared with mentally healthy individuals, marked by DCX+ cells (immature neurons) failing to produce other structures characteristic of mature neurons. The same researchers also observed that such a phenomenon worsened as Alzheimers disease progressed but did not offer any explanation. This research proposal introduces an experiment that could reveal the mechanism behind the decrease of adult hippocampal neurogenesis in patients with Alzheimers disease. Focusing on A1-42, a hallmark of Alzheimers disease, this paper examines its role in reducing the number of new neurons produced. Techniques such as immunofluorescence, chromatin immunoprecipitation sequencing, and RNA sequencing are employed.

Mechanisms of Tau Protein in Alzheimers Disease Pathogenesis and Potential Therapeutic Strategies: A Brief Review

2025-06-20

Shunyao Xu | Theoretical and Natural Science

Under normal physiological conditions, tau protein can maintain the function of microtubules, while under pathological conditions, it dissociates from microtubules and aggregates, thereby disrupting microtubule function and ultimately leading to … Under normal physiological conditions, tau protein can maintain the function of microtubules, while under pathological conditions, it dissociates from microtubules and aggregates, thereby disrupting microtubule function and ultimately leading to neuronal damage and the development of neurodegenerative diseases. Under pathological conditions, tau protein undergoes modifications such as phosphorylation, acetylation, ubiquitination, and truncation. These changes lead to the formation of neurofibrillary tangles through various mechanisms and ultimately cause Alzheimer's disease. In response to these diverse pathogenic mechanisms, people have developed a variety of potential therapeutic approaches targeting the underlying causes, such as modulating autophagy, inhibiting tau protein aggregation, clearing tau protein and so on. These studies demonstrate that the progression of neurodegenerative diseases, headed by Alzheimer's disease (AD), can be inhibited. This article aims to discuss the limitations in the aforementioned mechanisms and their corresponding therapeutic approaches, and to explore whether there are methods and ideas to address these shortcomings. Regrettably, the current potential therapeutic approaches are still unable to completely cure Alzheimer's disease, and the conditions required for treatment are rather demanding. However, these therapeutic methods may potentially serve as means for the early diagnosis and prevention of Alzheimer's disease. This article may provide more ideas for new therapeutic approaches to AD and other neurodegenerative diseases.

Mutations in PSEN1 predispose inflammation in an astrocyte model of familial Alzheimer’s disease through disrupted regulated intramembrane proteolysis

2025-06-20

Oliver J. Ziff , Gustavo Morrone Parfitt , Sarah Jolly +7 more | Molecular Neurodegeneration

Mutations in PSEN1 cause familial Alzheimer's disease with almost complete penetrance. Age at onset is highly variable between different PSEN1 mutations and even within families with the same mutation. Current … Mutations in PSEN1 cause familial Alzheimer's disease with almost complete penetrance. Age at onset is highly variable between different PSEN1 mutations and even within families with the same mutation. Current research into late onset Alzheimer's disease implicates inflammation in both disease onset and progression. PSEN1 is the catalytic subunit of γ-secretase, responsible for regulated intramembrane proteolysis of numerous substrates that include cytokine receptors. For this reason, we tested the hypothesis that mutations in PSEN1 impact inflammatory responses in astrocytes, thereby contributing to disease progression. We developed patient-derived models of iPSC-astrocytes, representing three lines harbouring PSEN1 mutations and six control lines (including two isogenic controls). Transcriptomic and biochemical assays were used to investigate differential inflammatory responses to TNFα, IL1α and C1Q. We show that PSEN1 is upregulated in response to inflammatory stimuli, and this upregulation is disrupted by pathological PSEN1 mutations. Using transcriptomic analyses, we demonstrate that PSEN1 mutant astrocytes have an augmented inflammatory profile in their basal state, concomitant with gene expression signatures revealing dysregulated intramembrane proteolysis and JAK-STAT signalling. Detailed investigation of the JAK-STAT2 signalling pathway showed reduced cell surface expression of IFNAR2, lower STAT2 phosphorylation cascades and delayed NFκB nuclear localisation in PSEN1 mutant astrocytes in response to inflammatory stimuli, thereby implicating the notion of altered cytokine signalling cascades. Finally, we use small molecule modulators of γ-secretase to confirm a role for PSEN1/γ-secretase in regulating the astrocytic response to inflammatory stimuli. Together, these data suggest that mutations in PSEN1 enhance cytokine signalling via impaired regulated intramembrane proteolysis, thereby predisposing astrocytic inflammatory profiles. These findings support a two-hit contribution of PSEN1 mutations to fAD pathogenesis, not only impacting APP and Aβ processing but also altering the cellular response to inflammation.

High-Throughput Screening of Amyloid Inhibitors via Covalent-Labeling Mass Spectrometry

2025-06-19

Kanitin Khamnong , Vanessa L. Stahl , Olivia N. Izikson +3 more | Analytical Chemistry

Amyloid fibril formation by proteins is implicated in numerous human diseases, yet few treatments exist in part due to the lack of robust screening methods for amyloid inhibitors. Here, we … Amyloid fibril formation by proteins is implicated in numerous human diseases, yet few treatments exist in part due to the lack of robust screening methods for amyloid inhibitors. Here, we demonstrate a novel mass spectrometry (MS) assay for high-throughput screening of amyloid inhibitors, based on measuring the extent of protein labeling during protein aggregation. Amyloid formation decreases covalent labeling (CL) extents, while the presence of an inhibitor restores the extent of labeling, providing a means of identifying inhibitors. Using two different labeling reagents, α,β-unsaturated carbonyl (ABUC) and diethylpyrocarbonate (DEPC), and insulin and β2-microglobulin (β2m) as model amyloid proteins, we show that the CL-MS assay can probe protein amyloid formation and its inhibition by a wide range of compounds, with validation achieved by comparisons to traditional fluorescence and light scattering techniques. In proof-of-concept screens, several new inhibitors are identified for both proteins and further verified for their ability to fully prevent aggregation. Overall, our CL-MS assay offers fewer false positives than conventional methods and is compatible with high-throughput screening, achieving rates of >10 compounds per minute using matrix-assisted laser desorption/ionization (MALDI)-MS as a readout.

History repeats itself: A new trivializing term for a potentially life-threatening side effect of antibody Alzheimer's disease therapy

2025-06-19

Poul Flemming Høilund‐Carlsen , Jorge R. Barrio | Journal of Alzheimer s Disease

The term “amyloid-removal-related pseudo-atrophy” has recently been proposed for the accelerated brain volume loss caused by anti-Alzheimer's antibody therapies, although most trials seem to neglect it. As with ‘amyloid-related imaging … The term “amyloid-removal-related pseudo-atrophy” has recently been proposed for the accelerated brain volume loss caused by anti-Alzheimer's antibody therapies, although most trials seem to neglect it. As with ‘amyloid-related imaging abnormalities’ (ARIAs), this is downplaying yet another side effect of passive antibody therapy that cannot be justified until its impact on brain function is fully understood. ARIAs and accelerated volume loss are likely due to antibody-induced brain tissue damage, making amyloid-PET imaging an unreliable indicator of amyloid removal. Therefore, approval of antibody therapy based on presumed amyloid removal should be suspended until this looming possibility has been fully investigated.

Back to the Future: Predicting Individual Tau Progression in Alzheimer’s Disease

2025-06-19

Robin Sandell , Justin Torok , Kamalini G. Ranasinghe +2 more | Research Square (Research Square)

Alzheimer's Disease (AD) is characterized by the spread of tau neurofibrillary tangles along the brain's structural network. The marked variability in pathology spread patterns across individuals necessitates a precision medicine … Alzheimer's Disease (AD) is characterized by the spread of tau neurofibrillary tangles along the brain's structural network. The marked variability in pathology spread patterns across individuals necessitates a precision medicine approach. Here we introduce Stage-based Network Diffusion (StaND), a novel algorithm that combines statistical staging with biophysical modeling to predict patient-specific tau progression. Using data from 650 subjects in the Alzheimer's Disease Neuroimaging Initiative, StaND first estimates each subject's disease stage and then infers their individual tau seeding pattern, agglomeration rate, and transmission rate. The model is applied forward in time to predict regional tau distributions cross-sectionally and longitudinally. StaND outperforms benchmark models in both instances. Inferred tau seed patterns capture spatial heterogeneity, while rate parameters explain temporal and cognitive variability. Despite diverse initial seeding patterns, tau distributions converge across subjects over time. We also identify two distinct tau seeding archetypes with distinct clinical and demographic profiles. StaND offers a powerful new approach for understanding and forecasting the spatiotemporal dynamics of AD and is widely applicable to other neurodegenerative diseases.

Pathogenic landscape shaped by cerebral amyloid oligomers

2025-06-19

Yujing Huang , Mengze Xu , Zhen Yuan +1 more | Neural Regeneration Research

Dysregulation of Inositol Polyphosphate 5-Phosphatase OCRL in Alzheimer’s Disease: Implications for Autophagy Dysfunction

2025-06-18

Kunié Ando , May Thazin Htut , Eugenia Maria Antonelli +7 more | International Journal of Molecular Sciences

Autophagy is impaired in Alzheimer's disease (AD), particularly at the stage of autophagosome-lysosome fusion. Recent studies suggest that the inositol polyphosphate 5-phosphatase OCRL (Lowe oculocerebrorenal syndrome protein) is involved in … Autophagy is impaired in Alzheimer's disease (AD), particularly at the stage of autophagosome-lysosome fusion. Recent studies suggest that the inositol polyphosphate 5-phosphatase OCRL (Lowe oculocerebrorenal syndrome protein) is involved in this fusion process; however, its role in AD pathophysiology remains largely unclear. In this study, we investigated the localization and expression of OCRL in post-mortem AD brains and in a 5XFAD transgenic mouse model. While OCRL RNA levels were not significantly altered, OCRL protein was markedly reduced in the RIPA-soluble fraction and positively correlated with the autophagy marker Beclin1. Immunohistochemical analysis revealed OCRL immunoreactivity in neuronal cytoplasm, granulovacuolar degeneration bodies, and plaque-associated dystrophic neurites in AD brains. Furthermore, OCRL overexpression in a FRET-based tau biosensor cell model significantly reduced the tau-seeding-induced FRET signal. These findings suggest that OCRL dysregulation may contribute to autophagic deficits and the progression of tau pathology in AD.

Bibliometric analysis of neural injury biomarkers in neurodegenerative diseases: research trends and future perspectives

2025-06-18

Chengzhou Pa , Shijun Shen , Yi Dai +1 more | Frontiers in Human Neuroscience

Introduction Neurodegenerative diseases (NDs) are progressive disorders with an increasing global health impact. Neural injury biomarkers have emerged as potential tools for early diagnosis and disease monitoring. Methods To map … Introduction Neurodegenerative diseases (NDs) are progressive disorders with an increasing global health impact. Neural injury biomarkers have emerged as potential tools for early diagnosis and disease monitoring. Methods To map research trends in this field, we conducted a comprehensive bibliometric analysis of 1,228 peer-reviewed articles published from 1991 to 2024 using CiteSpace and the Bibliometrix R package. Results Our analysis revealed steady publication growth, particularly accelerating after 2015. The United States, United Kingdom, and China produced the highest volume of publications and citations, with institutions such as the University of California System and Harvard University serving as key collaboration hubs. Early research prioritized tau, amyloid-beta (Aβ), cerebrospinal fluid (CSF), and mild cognitive impairment (MCI). Since 2020, the focus has expanded to blood-based biomarkers, exosomal microRNAs, and inflammation-related markers such as glial fibrillary acidic protein (GFAP) and translocator protein (TSPO). Through citation and clustering analyses, we identified three developmental phases: (1) CSF-based amyloid/tau validation, (2) multimodal and genetic biomarker integration, and (3) the emergence of plasma and neuroinflammatory markers. Discussion These trends reflect a paradigm shift toward minimally invasive and multifactorial diagnostic approaches. Our findings underscore evolving priorities in NDs biomarker research and highlight the importance of multi-omics, artificial intelligence (AI), and interdisciplinary collaboration for translational discovery and clinical application.

Detection of Alzheimer's Disease Neuropathology in Chronic Kidney Disease: Current State and Future Directions

2025-06-17

Aditi Gupta , Michelle M. Mielke , Pierre N. Tariot | Journal of the American Geriatrics Society

ABSTRACT The prevalence of both chronic kidney disease (CKD) and Alzheimer's disease (AD) increases with age. With the rise in average life expectancy, clinicians will be more likely to encounter … ABSTRACT The prevalence of both chronic kidney disease (CKD) and Alzheimer's disease (AD) increases with age. With the rise in average life expectancy, clinicians will be more likely to encounter patients with both CKD and cognitive concerns, including some with AD neuropathology. The prevalence of AD neuropathology and the nature of the interaction between AD neuropathology and vascular brain alterations in individuals with CKD are unclear. AD blood‐based biomarkers (BBM) are promising tools for detecting AD neuropathology and are being reviewed by the FDA for clinical use. However, AD BBMs do not perform reliably in CKD and can be elevated even in the absence of AD neuropathology (false positive). AD cerebrospinal fluid (CSF) biomarkers are also altered in CKD, further complicating the detection of AD neuropathology in this population. It is important for clinicians to understand the limitations of AD BBMs and perhaps CSF biomarkers in the real world, where there is a higher prevalence of CKD and other comorbidities compared to the population samples in which they have been studied. Even if the prevalence of AD neuropathology in CKD is not higher than that in the general population, it is important to accurately detect AD neuropathology among individuals with CKD, so that the new anti‐amyloid monoclonal antibodies can be used appropriately. This special article addresses the concerns with the use of AD BBM in the detection of AD neuropathology and the caution needed while using AD BBMs in clinical care.

Evidence that cholinergic mechanisms contribute to hyperexcitability at early stages in Alzheimer’s disease

2025-06-17

Helen E. Scharfman , Korey Kam , Áine Duffy +5 more | Frontiers in Dementia

A long-standing theory for Alzheimer’s disease (AD) has been that deterioration of synapses and depressed neuronal activity is a major contributing factor. We review the increasing evidence, in humans and … A long-standing theory for Alzheimer’s disease (AD) has been that deterioration of synapses and depressed neuronal activity is a major contributing factor. We review the increasing evidence, in humans and in mouse models, that show that there is often neuronal hyperactivity at early stages rather than decreased activity. We discuss studies in mouse models showing that hyperexcitability can occur long before plaque deposition and memory impairment. In mouse models, a generator of the hyperactivity appears to be the dentate gyrus. We present evidence, based on mouse models, that inhibition of muscarinic cholinergic receptors or medial septal cholinergic neurons can prevent hyperactivity. Therefore, we hypothesize the novel idea that cholinergic neurons are overly active early in the disease, not depressed. In particular we suggest the medial septal cholinergic neurons are overly active and contribute to hyperexcitability. We further hypothesize that the high activity of cholinergic neurons at early ages ultimately leads to their decline in function later in the disease. We review the effects of a prenatal diet that increases choline, the precursor to acetylcholine and modulator of many other functions. In mouse models of AD, maternal choline supplementation (MCS) reduces medial septal cholinergic pathology, amyloid accumulation and hyperexcitability, especially in the dentate gyrus, and improves cognition.

Role of Galangin for the Treatment of Alzheimer’s Disease: Journey So Far and Road Ahead

2025-06-17

Prince Sharma , Tripti Sharma , Bushra Bashir +7 more | Current Nutrition Reports

A Quantitative Systems Pharmacology Model That Describes Neurofilament Light Dynamics During Alzheimer's Disease Progression

2025-06-17

Polina Maliukova , Tatiana Karelina | CPT Pharmacometrics & Systems Pharmacology

Bibliometric analysis of the interplay between Alzheimer's disease and type 2 diabetes mellitus: Trends, hotspots, and emerging research areas

2025-06-17

Ming Cheng , Ya-Dong Wei , X. W. Zheng +3 more | Journal of Alzheimer s Disease

Background Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are major global health concerns, characterized by rising prevalence, high healthcare costs, and significant reductions in patients’ quality of life. … Background Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are major global health concerns, characterized by rising prevalence, high healthcare costs, and significant reductions in patients’ quality of life. Emerging evidence suggests that individuals with T2DM have nearly double the risk of developing AD, potentially due to overlapping mechanisms such as insulin resistance, oxidative stress, and neuroinflammation. Objective This study aims to systematically explore the evolving research landscape at the intersection of T2DM and AD over the past two decades, identifying major contributors, shifting research focuses, and emerging trends to inform future investigations and therapeutic development. Methods A comprehensive bibliometric analysis was conducted using data retrieved from the Web of Science Core Collection (WoSCC) spanning 2000 to 2024. A total of 3087 publications were analyzed using CiteSpace and the R package bibliometrix to assess publication trends, collaborative networks, and thematic evolution. Results The number of publications has steadily increased, with the United States and China emerging as dominant contributors. Institutions such as the University of California and Harvard University led in productivity and influence. Early research emphasized broad risk factors and cardiovascular comorbidities, while recent studies have shifted toward molecular mechanisms, particularly insulin resistance, neurodegeneration, and oxidative stress. Conclusions This 24-year bibliometric overview reveals a dynamic and expanding research field linking T2DM and AD. The findings highlight key geographic and institutional contributors, evolving thematic foci, and knowledge gaps, offering a valuable foundation for future research and potential therapeutic innovations.

A coupled mathematical and numerical model for protein spreading and tissue atrophy applied to Alzheimer’s disease

2025-06-17

Valentina Pederzoli , Mattia Corti , Davide Riccobelli +1 more | Computer Methods in Applied Mechanics and Engineering