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Neuroinflammation and Neurodegeneration Mechanisms

Works Count: 61575

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Description

This cluster of papers focuses on the role of microglia, neuroinflammation, and neurodegeneration in various neurological disorders such as Alzheimer's disease, ischemic stroke, and traumatic brain injury. It also explores the involvement of astrocytes, synaptic pruning, TREM2, cytokines, and innate immunity in the pathophysiology of these disorders.

Keywords

Microglia; Neuroinflammation; Neurodegeneration; Astrocytes; Synaptic Pruning; Ischemic Stroke; TREM2; Cytokines; Brain Development; Innate Immunity

Host microbiota constantly control maturation and function of microglia in the CNS

2015-06-01

Daniel Erny , Anna Lena Hrabě de Angelis , Diego Adhemar Jaitin +7 more

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Microglial <scp>M1/M2</scp> polarization and metabolic states

2015-03-20

Rubén Orihuela , Christopher A. McPherson , G. Jean Harry

Microglia are critical nervous system‐specific immune cells serving as tissue‐resident macrophages influencing brain development, maintenance of the neural environment, response to injury and repair. As influenced by their environment, microglia … Microglia are critical nervous system‐specific immune cells serving as tissue‐resident macrophages influencing brain development, maintenance of the neural environment, response to injury and repair. As influenced by their environment, microglia assume a diversity of phenotypes and retain the capability to shift functions to maintain tissue homeostasis. In comparison with peripheral macrophages, microglia demonstrate similar and unique features with regards to phenotype polarization, allowing for innate immunological functions. Microglia can be stimulated by LPS or IFN ‐ γ to an M 1 phenotype for expression of pro‐inflammatory cytokines or by IL‐4/IL‐13 to an M 2 phenotype for resolution of inflammation and tissue repair. Increasing evidence suggests a role of metabolic reprogramming in the regulation of the innate inflammatory response. Studies using peripheral immune cells demonstrate that polarization to an M 1 phenotype is often accompanied by a shift in cells from oxidative phosphorylation to aerobic glycolysis for energy production. More recently, the link between polarization and mitochondrial energy metabolism has been considered in microglia. Under these conditions, energy demands would be associated with functional activities and cell survival and thus, may serve to influence the contribution of microglia activation to various neurodegenerative conditions. This review examines the polarization states of microglia and their relationship to mitochondrial metabolism. Additional supporting experimental data are provided to demonstrate mitochondrial metabolic shifts in primary microglia and the BV ‐2 microglia cell line induced under LPS ( M1 ) and IL ‐4/ IL‐13 ( M2 ) polarization. Linked Articles This article is part of a themed section on Inflammation: maladies, models, mechanisms and molecules. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2016.173.issue-4

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Mechanisms Underlying Inflammation in Neurodegeneration

2010-03-01

Christopher K. Glass , Kaoru Saijo , Beate Winner +2 more

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Reactive microglia are positive for HLA‐DR in the substantia nigra of Parkinson's and Alzheimer's disease brains

1988-08-01

Patrick L. McGeer , Shigeru Itagaki , Barry E. Boyes +1 more

We detected large numbers of HLA-DR-positive reactive microglia (macrophages), along with Lewy bodies and free melanin, in the substantia nigra of all cases studied with Parkinson9s disease (5) and parkinsonism … We detected large numbers of HLA-DR-positive reactive microglia (macrophages), along with Lewy bodies and free melanin, in the substantia nigra of all cases studied with Parkinson9s disease (5) and parkinsonism with dementia (PD) (5). We found similar, but less extensive, pathology in the substantia nigra of six of nine cases of dementia of the Alzheimer type (DAT) but in only one of 11 age-matched nonneurologic cases. All dementia cases with a premortem diagnosis of DAT or PD showed large numbers of HLA-DR-positive reactive microglia and significant plaque and tangle counts in the hippocampus, as well as reduced cortical choline acetyltransferase activity. One of 11 nondemented controls showed mild evidence of similar cortical pathology. These data indicate that HLA-DR-positive reactive microglia are a sensitive index of neuropathologic activity. They suggest a frequent coexistence of DAT- and Parkinson-type pathology in elderly patients.

Synaptic Pruning by Microglia Is Necessary for Normal Brain Development

2011-07-22

Rosa Chiara Paolicelli , Giulia Bolasco , Francesca Pagani +7 more

A good brain needs a good vacuum cleaner. A good brain needs a good vacuum cleaner.

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Temporal profile of neuronal damage in a model of transient forebrain ischemia

1982-05-01

William A. Pulsinelli , J. B. Brierley , Fred Plum

Abstract This study examined the temporal profile of ischemic neuronal damage following transient bilateral forebrain ischemia in the rat model of four‐vessel occlusion. Wistar rats were subjected to transient but … Abstract This study examined the temporal profile of ischemic neuronal damage following transient bilateral forebrain ischemia in the rat model of four‐vessel occlusion. Wistar rats were subjected to transient but severe forebrain ischemia by permanently occluding the vertebral arteries and 24 hours later temporarily occluding the common carotid arteries for 10, 20, or 30 minutes. Carotid artery blood flow was restored and the rats were killed by perfusion‐fixation after 3, 6, 24, and 72 hours. Rats with postischemic convulsions were discarded. Ischemic neuronal damage was graded in accordance with conventional neuropathological criteria. Ten minutes of four‐vessel occlusion produced scattered ischemic cell change in the cerebral hemispheres of most rats. The time to onset of visible neuronal damage varied among brain regions and in some regions progressively worsened with time. After 30 minutes of ischemia, small to medium‐sized striatal neurons were damaged early while the initiation of visible damage to hippocampal neurons in the h1 zone was delayed for 3 to 6 hours. The number of damaged neurons in neocortex (layer 3, layers 5 and 6, or both) and hippocampus (h1, h3–5, paramedian zone) increased significantly ( p < 0.01) between 24 and 72 hours. The unique delay in onset of ischemic cell change and the protracte increase in its incidence between 24 and 72 hours could reflect either delayed‐appearance of ischemic change in previously killed neurons or a delayed insult that continued to jeopardize compromised but otherwise viable neurons during the postischemic period.

Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain

1990-01-01

L.J. Lawson , V. Hugh Perry , Pietro Dri +1 more

Copper-Zinc Superoxide Dismutase (SOD1) Is Released by Microglial Cells and Confers Neuroprotection against 6-OHDA Neurotoxicity

2012-05-09

Elisabetta Polazzi , Ilaria Mengoni , Marco Caprini +3 more

The role so far ascribed to intracellular CuZn superoxide dismutase is that of an intracellular scavenger of oxygen radicals. However, other functions of cytosolic CuZn superoxide dismutase have been hypothesized. … The role so far ascribed to intracellular CuZn superoxide dismutase is that of an intracellular scavenger of oxygen radicals. However, other functions of cytosolic CuZn superoxide dismutase have been hypothesized. For example, CuZn superoxide dismutase incubated with rat hepatocyte cells in culture inhibits 3-hydroxy-3methylglutaryl CoA reductase, thereby reducing cholesterol synthesis. We recently demonstrated the presence of surface membrane receptors for CuZn superoxide dismutase, suggesting possible autocrine or paracrine activities. The aim of the present study was to investigate whether cytosolic CuZn superoxide dismutase can be secreted by human hepatocarcinoma and fibroblast cells lines. Proteins in human hepatocellular carcinoma (Hep G2) cells and human fibroblasts were biosynthetically labelled with [35S]-cysteine; then cell lysates and media were immunoprecipitated with rabbit polyclonal anti-human CuZn superoxide dismutase antibodies and separated by 12% polyacrylamide gel electrophoresis. Both Hep G2 cells and human fibroblasts produce and secrete CuZn superoxide dismutase which was detectable in cells and medium as a single protein band with the same electrophoretic mobility as human erythrocyte CuZn superoxide dismutase. These data suggest that CuZn superoxide dismutase, an enzyme thus far considered to be located exclusively intracellularly is secreted by at least two cell lines. This is consistent with autocrine or paracrine roles for CuZn superoxide dismutase.

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Microglia: active sensor and versatile effector cells in the normal and pathologic brain

2007-10-26

Uwe‐Karsten Hanisch , Helmut Kettenmann

Microglia-mediated neurotoxicity: uncovering the molecular mechanisms

2006-12-20

Michelle L. Block , Luigi Zecca , Jau‐Shyong Hong

Glutamate neurotoxicity and diseases of the nervous system

1988-10-01

Dennis W. Choi

A gene expression atlas of the central nervous system based on bacterial artificial chromosomes

2003-10-01

Shiaoching Gong , Zheng Chen , Martin L. Doughty +7 more

Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner

2012-05-01

Dorothy P. Schafer , Emily K. Lehrman , Amanda G. Kautzman +7 more

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LEUKOCYTE LOCOMOTION AND CHEMOTAXIS

1973-02-01

Sally H. Zigmond , James G. Hirsch

Polymorphonuclear leukocyte (PMN) locomotion and chemotaxis have been evaluated by direct microscopic observation of individual cells in thin slide-cover slip preparations, and also by observations on populations of cells migrating … Polymorphonuclear leukocyte (PMN) locomotion and chemotaxis have been evaluated by direct microscopic observation of individual cells in thin slide-cover slip preparations, and also by observations on populations of cells migrating into a Millipore filter. The direct microscopic method used the polarity of the locomoting PMNs (broad, advancing lamellipodium and knoblike constriction at the rear) to record the direction of movement. The Boyden chamber Millipore assay was made more reliable by following the front of cells advancing into the filter, rather than counting the number of cells on the lower filter surface. Special modifications of the Millipore assay were necessary in order to distinguish between influences on rate of locomotion and true chemotaxis. In both systems the results indicate that under certain conditions leukocytes, and in particular PMNs, release into the medium a factor stimulating locomotion and exerting chemotactic action on PMNs in the vicinity. This cell-derived factor appears not to require serum factors for its release or action.

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Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration

2007-01-03

Liya Qin , Xuefei Wu , Michelle L. Block +5 more

Abstract Inflammation is implicated in the progressive nature of neurodegenerative diseases, such as Parkinson's disease, but the mechanisms are poorly understood. A single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) or … Abstract Inflammation is implicated in the progressive nature of neurodegenerative diseases, such as Parkinson's disease, but the mechanisms are poorly understood. A single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) or tumor necrosis factor alpha (TNFα, 0.25 mg/kg, i.p.) injection was administered in adult wild‐type mice and in mice lacking TNFα receptors (TNF R1/R2 −/− ) to discern the mechanisms of inflammation transfer from the periphery to the brain and the neurodegenerative consequences. Systemic LPS administration resulted in rapid brain TNFα increase that remained elevated for 10 months, while peripheral TNFα (serum and liver) had subsided by 9 h (serum) and 1 week (liver). Systemic TNFα and LPS administration activated microglia and increased expression of brain pro‐inflammatory factors (i.e., TNFα, MCP‐1, IL‐1β, and NF‐κB p65) in wild‐type mice, but not in TNF R1/R2 −/− mice. Further, LPS reduced the number of tyrosine hydroxylase‐immunoreactive neurons in the substantia nigra (SN) by 23% at 7‐months post‐treatment, which progressed to 47% at 10 months. Together, these data demonstrate that through TNFα, peripheral inflammation in adult animals can: (1) activate brain microglia to produce chronically elevated pro‐inflammatory factors; (2) induce delayed and progressive loss of DA neurons in the SN. These findings provide valuable insight into the potential pathogenesis and self‐propelling nature of Parkinson's disease. © 2007 Wiley‐Liss, Inc.

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Physiology of Microglia

2011-04-01

Helmut Kettenmann , Uwe‐Karsten Hanisch , Mami Noda +1 more

Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through the brain parenchyma, … Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through the brain parenchyma, and acquire a specific ramified morphological phenotype termed “resting microglia.” Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways they can communicate with macroglial cells and neurons and with cells of the immune system. Likewise, microglial cells express receptors classically described for brain-specific communication such as neurotransmitter receptors and those first discovered as immune cell-specific such as for cytokines. Microglial cells are considered the most susceptible sensors of brain pathology. Upon any detection of signs for brain lesions or nervous system dysfunction, microglial cells undergo a complex, multistage activation process that converts them into the “activated microglial cell.” This cell form has the capacity to release a large number of substances that can act detrimental or beneficial for the surrounding cells. Activated microglial cells can migrate to the site of injury, proliferate, and phagocytose cells and cellular compartments.

Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases

2015-01-19

Yu Tang , Weidong Le

Astrocytes: biology and pathology

2009-12-09

Michael V. Sofroniew , Harry V. Vinters

Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. … Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to long-lasting scar formation with rearrangement of tissue structure. Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions.

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Genomic Analysis of Reactive Astrogliosis

2012-05-02

Jennifer Zamanian , Lijun Xu , Lynette C. Foo +4 more

Reactive astrogliosis is characterized by a profound change in astrocyte phenotype in response to all CNS injuries and diseases. To better understand the reactive astrocyte state, we used Affymetrix GeneChip … Reactive astrogliosis is characterized by a profound change in astrocyte phenotype in response to all CNS injuries and diseases. To better understand the reactive astrocyte state, we used Affymetrix GeneChip arrays to profile gene expression in populations of reactive astrocytes isolated at various time points after induction using two mouse injury models, ischemic stroke and neuroinflammation. We find reactive gliosis consists of a rapid, but quickly attenuated, induction of gene expression after insult and identify induced Lcn2 and Serpina3n as strong markers of reactive astrocytes. Strikingly, reactive astrocyte phenotype strongly depended on the type of inducing injury. Although there is a core set of genes that is upregulated in reactive astrocytes from both injury models, at least 50% of the altered gene expression is specific to a given injury type. Reactive astrocytes in ischemia exhibited a molecular phenotype that suggests that they may be beneficial or protective, whereas reactive astrocytes induced by LPS exhibited a phenotype that suggests that they may be detrimental. These findings demonstrate that, despite well established commonalities, astrocyte reactive gliosis is a highly heterogeneous state in which astrocyte activities are altered to respond to the specific injury. This raises the question of how many subtypes of reactive astrocytes exist. Our findings provide transcriptome databases for two subtypes of reactive astrocytes that will be highly useful in generating new and testable hypotheses of their function, as well as for providing new markers to detect different types of reactive astrocytes in human neurological diseases.

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Molecular dissection of reactive astrogliosis and glial scar formation

2009-09-25

Michael V. Sofroniew

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Neuroinflammation in Alzheimer's disease

2015-03-16

Michael T. Heneka , Monica J. Carson , Joseph El Khoury +7 more

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Resting Microglial Cells Are Highly Dynamic Surveillants of Brain Parenchyma in Vivo

2005-04-15

Axel Nimmerjahn , Frank Kirchhoff , Fritjof Helmchen

Microglial cells represent the immune system of the mammalian brain and therefore are critically involved in various injuries and diseases. Little is known about their role in the healthy brain … Microglial cells represent the immune system of the mammalian brain and therefore are critically involved in various injuries and diseases. Little is known about their role in the healthy brain and their immediate reaction to brain damage. By using in vivo two-photon imaging in neocortex, we found that microglial cells are highly active in their presumed resting state, continually surveying their microenvironment with extremely motile processes and protrusions. Furthermore, blood-brain barrier disruption provoked immediate and focal activation of microglia, switching their behavior from patroling to shielding of the injured site. Microglia thus are busy and vigilant housekeepers in the adult brain.

Microglia Promote Learning-Dependent Synapse Formation through Brain-Derived Neurotrophic Factor

2013-12-01

Christopher N. Parkhurst , Guang Yang , Ipe Ninan +6 more

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Colony-Stimulating Factor 1 Receptor Signaling Is Necessary for Microglia Viability, Unmasking a Microglia Progenitor Cell in the Adult Brain

2014-04-01

Monica R. P. Elmore , Allison R. Najafi , Maya A. Koike +7 more

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Microglia: a sensor for pathological events in the CNS

1996-08-01

G. W. Kreutzberg

Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system

2007-10-31

Jean Livet , Tamily A. Weissman , Hyuno Kang +5 more

Microglial Physiology: Unique Stimuli, Specialized Responses

2009-03-20

Richard M. Ransohoff , V. Hugh Perry

Microglia, the macrophages of the central nervous system parenchyma, have in the normal healthy brain a distinct phenotype induced by molecules expressed on or secreted by adjacent neurons and astrocytes, … Microglia, the macrophages of the central nervous system parenchyma, have in the normal healthy brain a distinct phenotype induced by molecules expressed on or secreted by adjacent neurons and astrocytes, and this phenotype is maintained in part by virtue of the blood-brain barrier's exclusion of serum components. Microglia are continually active, their processes palpating and surveying their local microenvironment. The microglia rapidly change their phenotype in response to any disturbance of nervous system homeostasis and are commonly referred to as activated on the basis of the changes in their morphology or expression of cell surface antigens. A wealth of data now demonstrate that the microglia have very diverse effector functions, in line with macrophage populations in other organs. The term activated microglia needs to be qualified to reflect the distinct and very different states of activation-associated effector functions in different disease states. Manipulating the effector functions of microglia has the potential to modify the outcome of diverse neurological diseases.

The immunology of stroke: from mechanisms to translation

2011-07-01

Costantino Iadecola , Josef Anrather

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ATP mediates rapid microglial response to local brain injury in vivo

2005-05-15

Dimitrios Davalos , Jaime Grutzendler , Guang Yang +6 more

<i>TREM2</i> Variants in Alzheimer's Disease

2012-11-15

Rita Guerreiro , Aleksandra Wojtas , José Brás +7 more

Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia. Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia.

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Identification of a unique TGF-β–dependent molecular and functional signature in microglia

2013-12-08

Oleg Butovsky , Mark P. Jedrychowski , Craig S. Moore +7 more

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Reactive astrocytes: cellular and molecular cues to biological function

1997-12-01

Jean‐Luc Ridet , Alain Privat , S. K. Malhotra +1 more

Fate Mapping Analysis Reveals That Adult Microglia Derive from Primitive Macrophages

2010-10-22

Florent Ginhoux , Melanie Greter , Marylène Leboeuf +7 more

Microglia are the resident macrophages of the central nervous system and are associated with the pathogenesis of many neurodegenerative and brain inflammatory diseases; however, the origin of adult microglia remains … Microglia are the resident macrophages of the central nervous system and are associated with the pathogenesis of many neurodegenerative and brain inflammatory diseases; however, the origin of adult microglia remains controversial. We show that postnatal hematopoietic progenitors do not significantly contribute to microglia homeostasis in the adult brain. In contrast to many macrophage populations, we show that microglia develop in mice that lack colony stimulating factor-1 (CSF-1) but are absent in CSF-1 receptor-deficient mice. In vivo lineage tracing studies established that adult microglia derive from primitive myeloid progenitors that arise before embryonic day 8. These results identify microglia as an ontogenically distinct population in the mononuclear phagocyte system and have implications for the use of embryonically derived microglial progenitors for the treatment of various brain disorders.

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The Cellular Phase of Alzheimer’s Disease

2016-02-01

Bart De Strooper , Eric Karran

New tools for studying microglia in the mouse and human CNS

2016-02-16

Mariko L. Bennett , F. Chris Bennett , Shane A. Liddelow +7 more

Significance Microglia are the tissue resident macrophages of the brain and spinal cord, implicated in important developmental, homeostatic, and disease processes, although our understanding of their roles is complicated by … Significance Microglia are the tissue resident macrophages of the brain and spinal cord, implicated in important developmental, homeostatic, and disease processes, although our understanding of their roles is complicated by an inability to distinguish microglia from related cell types. Although they share many features with other macrophages, microglia have distinct developmental origins and functions. Here we validate a stable and robustly expressed microglial marker for both mouse and human, transmembrane protein 119 (Tmem119). We use custom-made antibodies against Tmem119 to perform deep RNA sequencing of developing microglia, and demonstrate that microglia mature by the second postnatal week in mice. The antibodies, cell isolation methods, and RNAseq profiles presented here will greatly facilitate our understanding of microglial function in health and disease.

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Complement and microglia mediate early synapse loss in Alzheimer mouse models

2016-04-01

Soyon Hong , Victoria F. Beja-Glasser , Bianca M. Nfonoyim +7 more

Too much cleaning up The complement system and microglia seek out and destroy unwanted cellular debris for the peripheral immune system as well as excess synapses in the developing brain. … Too much cleaning up The complement system and microglia seek out and destroy unwanted cellular debris for the peripheral immune system as well as excess synapses in the developing brain. Hong et al. now show how the system may go haywire in adults early in the progression toward Alzheimer's disease (AD). Aberrant synapse loss is an early feature of Alzheimer's and correlates with cognitive decline. In mice susceptible to AD, complement was associated with synapses, and microglial function was required for synapse loss. The authors speculate that aberrant activation of this “trash disposal” system underlies AD pathology. Science , this issue p. 712

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How neuroinflammation contributes to neurodegeneration

2016-08-18

Richard M. Ransohoff

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal lobar dementia are among the most pressing problems of developed societies with aging populations. Neurons carry out … Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal lobar dementia are among the most pressing problems of developed societies with aging populations. Neurons carry out essential functions such as signal transmission and network integration in the central nervous system and are the main targets of neurodegenerative disease. In this Review, I address how the neuron's environment also contributes to neurodegeneration. Maintaining an optimal milieu for neuronal function rests with supportive cells termed glia and the blood-brain barrier. Accumulating evidence suggests that neurodegeneration occurs in part because the environment is affected during disease in a cascade of processes collectively termed neuroinflammation. These observations indicate that therapies targeting glial cells might provide benefit for those afflicted by neurodegenerative disorders.

Microglia Function in the Central Nervous System During Health and Neurodegeneration

2017-02-22

Marco Colonna , Oleg Butovsky

Microglia are resident cells of the brain that regulate brain development, maintenance of neuronal networks, and injury repair. Microglia serve as brain macrophages but are distinct from other tissue macrophages … Microglia are resident cells of the brain that regulate brain development, maintenance of neuronal networks, and injury repair. Microglia serve as brain macrophages but are distinct from other tissue macrophages owing to their unique homeostatic phenotype and tight regulation by the central nervous system (CNS) microenvironment. They are responsible for the elimination of microbes, dead cells, redundant synapses, protein aggregates, and other particulate and soluble antigens that may endanger the CNS. Furthermore, as the primary source of proinflammatory cytokines, microglia are pivotal mediators of neuroinflammation and can induce or modulate a broad spectrum of cellular responses. Alterations in microglia functionality are implicated in brain development and aging, as well as in neurodegeneration. Recent observations about microglia ontogeny combined with extensive gene expression profiling and novel tools to study microglia biology have allowed us to characterize the spectrum of microglial phenotypes during development, homeostasis, and disease. In this article, we review recent advances in our understanding of the biology of microglia, their contribution to homeostasis, and their involvement in neurodegeneration. Moreover, we highlight the complexity of targeting microglia for therapeutic intervention in neurodegenerative diseases.

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Neurotoxic reactive astrocytes are induced by activated microglia

2017-01-01

Shane A. Liddelow , Kevin A. Guttenplan , Laura Clarke +7 more

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A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease

2017-06-01

Hadas Keren‐Shaul , Amit Spinrad , Assaf Weiner +7 more

Reactive Astrocytes: Production, Function, and Therapeutic Potential

2017-06-01

Shane A. Liddelow , Ben A. Barres

The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases

2017-09-01

Susanne Krasemann , Charlotte Madore , Ron Cialic +7 more

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Microglia and macrophages in brain homeostasis and disease

2017-11-20

Qingyun Li , Ben A. Barres

Mechanisms, challenges and opportunities in stroke

2003-05-01

Eng H. Lo , Turgay Dalkara , Michael A. Moskowitz

Inflammation as a central mechanism in Alzheimer's disease

2018-01-01

Jefferson W. Kinney , Shane M. Bemiller , Andrew S. Murtishaw +3 more

Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by cognitive decline and the presence of two core pathologies, amyloid β plaques and neurofibrillary tangles. Over the … Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by cognitive decline and the presence of two core pathologies, amyloid β plaques and neurofibrillary tangles. Over the last decade, the presence of a sustained immune response in the brain has emerged as a third core pathology in AD. The sustained activation of the brain's resident macrophages (microglia) and other immune cells has been demonstrated to exacerbate both amyloid and tau pathology and may serve as a link in the pathogenesis of the disorder. In the following review, we provide an overview of inflammation in AD and a detailed coverage of a number of microglia‐related signaling mechanisms that have been implicated in AD. Additional information on microglia signaling and a number of cytokines in AD are also reviewed. We also review the potential connection of risk factors for AD and how they may be related to inflammatory mechanisms.

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Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes

2018-11-21

Timothy R. Hammond , Connor Dufort , Lasse Dissing‐Olesen +7 more

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Single-cell transcriptomic analysis of Alzheimer’s disease

2019-05-01

Hansruedi Mathys , José Dávila-Velderrain , Zhuyu Peng +7 more

Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes

2020-11-26

Hyuk Sung Kwon , Seong‐Ho Koh

Abstract Neuroinflammation is associated with neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Microglia and astrocytes are key regulators of inflammatory responses in the central nervous … Abstract Neuroinflammation is associated with neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Microglia and astrocytes are key regulators of inflammatory responses in the central nervous system. The activation of microglia and astrocytes is heterogeneous and traditionally categorized as neurotoxic (M1-phenotype microglia and A1-phenotype astrocytes) or neuroprotective (M2-phenotype microglia and A2-phenotype astrocytes). However, this dichotomized classification may not reflect the various phenotypes of microglia and astrocytes. The relationship between these activated glial cells is also very complicated, and the phenotypic distribution can change, based on the progression of neurodegenerative diseases. A better understanding of the roles of microglia and astrocytes in neurodegenerative diseases is essential for developing effective therapies. In this review, we discuss the roles of inflammatory response in neurodegenerative diseases, focusing on the contributions of microglia and astrocytes and their relationship. In addition, we discuss biomarkers to measure neuroinflammation and studies on therapeutic drugs that can modulate neuroinflammation.

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Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?

2020-12-14

Fangda Leng , Paul Edison

Reactive astrocyte nomenclature, definitions, and future directions

2021-02-15

Carole Escartin , Elena Galea , András Lakatos +7 more

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Microglia loss triggers glial stress and white matter damage in human leukodystrophy

2025-06-26

| Nature Immunology

Cross-Sectional and Longitudinal Associations of Neighborhood Disadvantage With Fluid Biomarkers of Neuroinflammation and Neurodegeneration

2025-06-25

Marissa A. Gogniat , Omair A. Khan , Brina Ratangee +7 more | Neurology

Living in a socioeconomically disadvantaged neighborhood has an adverse impact on health outcomes, including increased risk of Alzheimer disease (AD). The biological mechanisms underlying this risk are poorly understood. We … Living in a socioeconomically disadvantaged neighborhood has an adverse impact on health outcomes, including increased risk of Alzheimer disease (AD). The biological mechanisms underlying this risk are poorly understood. We sought to examine how neighborhood disadvantage relates to core AD pathology, neurodegeneration, and inflammatory biomarkers in community-dwelling older adults cross-sectionally and over time. Participants included older adults from the Vanderbilt Memory and Aging Project who underwent fasting blood and CSF acquisition serially over a 9-year follow-up period (mean follow-up = 6.4 years [blood] and 4.0 years [CSF]). Area Deprivation Index (ADI), representing neighborhood disadvantage, was quantified at baseline using 17 components (e.g., housing, income, education, and household characteristics), with higher values indicating greater disadvantage. Ordinary least-squares regressions cross-sectionally related ADI to plasma and CSF inflammatory biomarkers adjusting for age, sex, race/ethnicity, education, modified Framingham Stroke Risk Profile score, APOE ε4 status, and cognitive status. Linear mixed-effects regression models related ADI to longitudinal biomarkers with identical covariates plus follow-up time. Outcomes included CSF chitinase-3-like protein 1 (YKL-40), CSF soluble-triggering receptor expressed on myeloid cells 2, CSF amyloid-β42 (Aβ42), CSF Aβ40/Aβ42 ratio, CSF tau, CSF phosphorylated tau (ptau), plasma high-sensitivity C-reactive protein (CRP), and plasma and CSF neurofilament light chain. Participants (n = 334; 73 ± 8 years old, 59% male, 86% White, non-Hispanic) on average were from relatively less disadvantaged neighborhoods (ADI national decile = 33 ± 25, range = 1-98). Greater neighborhood disadvantage at study entry was cross-sectionally associated with elevated CSF YKL-40 (β = 0.7, p = 0.003) and tau (β = 1.8, p = 0.04) after excluding outliers. Greater neighborhood disadvantage at study entry related to faster longitudinal increases in plasma CRP (β = 0.005, p = 0.03). Greater neighborhood disadvantage was associated with elevated inflammatory and AD CSF biomarkers cross-sectionally and longitudinal increases in a nonspecific inflammatory blood biomarker. Findings suggest that neighborhood disadvantage confers risk of systemic inflammation and AD pathology, providing a possible sociobiological mechanism underlying health disparities in aging adults; however, results were limited by use of ADI at study entry.

Dynamic microglia/macrophage infiltration during spinal cord regeneration in larval sea lamprey

2025-06-25

Eduardo Guadarrama , Logan W. Heisse , Jennifer R. Morgan +1 more | Annals of the New York Academy of Sciences

Abstract Both mammals and non‐mammalian vertebrates display neuroimmune interactions after spinal cord injury (SCI). However, the impact of the immune response on neural regeneration remains unclear as it includes both … Abstract Both mammals and non‐mammalian vertebrates display neuroimmune interactions after spinal cord injury (SCI). However, the impact of the immune response on neural regeneration remains unclear as it includes both proregenerative and inhibitory processes. To begin to understand how neuroimmune interactions influence central nervous system (CNS) regeneration, we examined the distribution of microglia/macrophages in relation to regenerating axons in larval sea lamprey ( Petromyzon marinus ), a non‐mammalian vertebrate that exhibits robust axon and synapse regeneration after SCI. The relationship between microglia/macrophages and spinal axons was examined in cryosections of control and transected spinal cords using immunofluorescence. SCI significantly increased microglia/macrophage density within the spinal cord, as shown by isolectin B 4 labeling. At 11 weeks post‐injury (WPI), microglia/macrophages made physical contacts with regenerating axons, on average a three‐fold increase compared to controls. These results are consistent with the conclusion that microglia/macrophage infiltration is associated with axon regeneration. Understanding the importance of these neuroimmune interactions could bring insight into cellular and molecular mechanisms that promote regeneration in the mammalian CNS.

Association of peripheral immune markers with brain age and dementia risk estimated using deep learning methods

2025-06-25

Xiaxuan Huang , Shiqi Yuan , Yitong Ling +6 more | International Journal of Surgery

Background: The peripheral immune system is essential for maintaining central nervous system homeostasis. This study investigates the effects of peripheral immune markers on accelerated brain aging and dementia using brain-predicted … Background: The peripheral immune system is essential for maintaining central nervous system homeostasis. This study investigates the effects of peripheral immune markers on accelerated brain aging and dementia using brain-predicted age difference based on neuroimaging. Methods: By leveraging data from the UK Biobank, Cox regression was used to explore the relationship between peripheral immune markers and dementia, and multivariate linear regression to assess associations between peripheral immune biomarkers and brain structure. Additionally, we established a brain age prediction model using Simple Fully Convolutional Network (SFCN) deep learning architecture. Analysis of the resulting brain-Predicted Age Difference (PAD) revealed relationships between accelerated brain aging, peripheral immune markers, and dementia. Results: During the median follow-up period of 14.3 years, 4, 277 dementia cases were observed among 322, 761 participants. Both innate and adaptive immune markers correlated with dementia risk. NLR showed the strongest association with dementia risk (HR = 1.14; 95% CI: 1.11-1.18, P<0.001). Multivariate linear regression revealed significant associations between peripheral immune markers and brain regional structural indices. Utilizing the deep learning-based SFCN model, the estimated brain age of dementia subjects (MAE = 5.63, r 2 = − 0.46, R = 0.22) was determined. PAD showed significant correlation with dementia risk and certain peripheral immune markers, particularly in individuals with positive brain age increment. Conclusion: This study employs brain age as a quantitative marker of accelerated brain aging to investigate its potential associations with peripheral immunity and dementia, highlighting the importance of early intervention targeting peripheral immune markers to delay brain aging and prevent dementia.

Beneficial role of GZMK+CD8+ T cells in neurodegeneration

2025-06-25

| Nature Immunology

Microglia promote inflammatory cell death upon neuronal mitochondrial impairment during neurodegeneration

2025-06-25

Guangyan Miao , Tina M. Fortier , Haibo Liu +4 more | Nature Structural & Molecular Biology

Neutrophil Mobilization Triggers Microglial Functional Change to Exacerbate Cerebral Ischemia‐Reperfusion Injury

2025-06-25

Huijuan Jin , Zhifang Li , Senwei Tan +7 more | Advanced Science

Abstract Acute ischemic stroke is a leading cause of mortality and disability worldwide. Neuroinflammation following ischemia‐reperfusion plays a critical role in the disease's pathogenesis. Neutrophil aggregation and clearance within the … Abstract Acute ischemic stroke is a leading cause of mortality and disability worldwide. Neuroinflammation following ischemia‐reperfusion plays a critical role in the disease's pathogenesis. Neutrophil aggregation and clearance within the brain parenchyma influence neuroinflammatory damage during ischemic stroke. Microglia‐mediated phagocytosis plays a pivotal role in mitigating neuroinflammation and promoting brain parenchyma recovery. However, the mechanisms underlying the cross‐talk between neutrophils and microglia remain poorly understood. Here, this study demonstrates that neutrophils can trigger microglial functional change to inhibit microglial phagocytosis and promote pyroptosis, which is regulated by neutrophil‐derived myeloid‐related protein 14. Additionally, interleukin‐1 β released by pyroptotic microglia further upregulates myeloid‐related protein 14 expression and facilitates neutrophil mobilization from the bone marrow, establishing a self‐sustaining inflammatory loop. Therefore, neutrophils accumulate in the brain parenchyma and further exacerbate microglial neuroinflammation in the ischemic brain. These findings reveal a previously unknown interaction between neutrophils and microglia after acute ischemic stroke and suggest that targeting myeloid‐related protein 14 may provide a novel therapeutic strategy for ischemic stroke therapy.

IFP35, a novel DAMP, aggravates neuroinflammation following acute ischemic stroke via TLR4/NF-κB/NLRP3 signaling

2025-06-25

Mengmeng Zhang , Bingnan Guo , Xiaowei Zhang +7 more | Journal of Neuroinflammation

Acute ischemic stroke is a disastrous disease characterized by damaging blood flow in the brain, leading to acute brain injury. Acute brain ischemia elicits severe inflammation, thus in turn, aggravates … Acute ischemic stroke is a disastrous disease characterized by damaging blood flow in the brain, leading to acute brain injury. Acute brain ischemia elicits severe inflammation, thus in turn, aggravates neural injury. Interferon-Induced Protein 35 (IFP35), is a 35 kDa protein, a novel type of DAMP that trigger inflammatory responses, exacerbating acute and chronic inflammatory disease. This study aimed to investigate the potential neuroinflammation role of IFP35 in acute ischemic stroke in a mouse model of MCAO. C57BL/6 male mice were subjected to middle cerebral artery occlusion (MCAO) to establish an animal model of acute ischemic stroke. Leveraging serum from stroke patients, serum and brain tissue after MCAO mice, IFP35 was released. Immunofluorescence assay was used to investigated the cell sources of IFP35 expression after MCAO. The impact of IFP35 on neuroinflammation and neural injury was assessed by siRNA-mediated cerebral IFP35 knockdown. Behavioral tests, and brain tissues were harvested for histological analysis and biochemical assays. TUNEL assays were used to evaluate neuronal damage. TTC staining was performed to assess infarction volumes. Additionally, using western blotting and immunofluorescence assays, we further assessed the contribution of TLR4/NF-κB/NLRP3 signaling in MCAO mice and BV2 cells. IFP35 was accumulated in peripheral blood of cerebral ischaemia patients, ischemia mice serum, as well as peri-infarct regions in focal cerebral ischemia mice. Although endothelial cells, microglia, and astrocytes are capable of expressing IFP35, cerebral neural cells seem to express and release more IFP35 compare to other cell types. Knockdown of IFP35 alleviated the production of neuroinflammatory cytokines, decreased neuronal death, and minimized infarct volumes, ultimately leading to improved neurological outcomes. Importantly, IFP35 triggered the activation of NF-κΒ and NLRP3 signaling, exacerbating neuroinflammation and brain injury by binding its receptor TLR4. This study revealed IFP35 as a novel DAMP released during cerebral ischemia that promotes neuroinflammation and injury, expanding the current understanding of inflammatory networks following stroke.

Bridging the Gap: The Neuro-immune Axis as a Key Player in Neurodegenerative Disorders

2025-06-25

Tingting Liu , Haojie Wu , Jianshe Wei | Neuroscience Bulletin

TNF-α-induced type I IFN signalling decreases neurogenesis and drives T cell chemotaxis

2025-06-24

Tinne A. D. Nissen , Abiyad Baig , D. Rock +6 more | bioRxiv (Cold Spring Harbor Laboratory)

Adult hippocampal neurogenesis (AHN) is essential for learning, memory, and mood regulation, and its disruption is implicated in ageing, neurodegeneration, and mood disorders. However, the mechanisms linking inflammation to AHN … Adult hippocampal neurogenesis (AHN) is essential for learning, memory, and mood regulation, and its disruption is implicated in ageing, neurodegeneration, and mood disorders. However, the mechanisms linking inflammation to AHN impairment remain unclear. Here, we identify chronic tumour necrosis factor-alpha (TNF-α) signalling as a key driver of neurogenic dysregulation via a previously unrecognized type I interferon (IFN) autocrine/paracrine loop in human hippocampal progenitor cells (HPCs). Using a human in vitro neurogenesis model, single-cell RNA sequencing, and functional T cell migration assays, we show that TNF-α induces a robust type I IFN response in HPCs, promoting chemokine and CXCR3-dependent T cell recruitment and suppressing neurogenesis. This inflammatory signalling cascade drives a fate switch in HPCs from a neurogenic trajectory towards an immune-defensive phenotype, with critical implications for infectious and inflammatory disease pathogenesis. These findings uncover a key inflammatory checkpoint regulating human AHN and highlight potential therapeutic targets to restore neurogenesis in chronic inflammatory states.

Identifying Microglia and Peripheral Infiltrating Macrophages in the Injured Spinal Cords Using Flow Cytometry

2025-06-24

Yuqing Chen , Jianxiong Gao , Hua-Zheng Yan +5 more | Journal of Visualized Experiments

Granzyme K+ CD8 T cells slow tauopathy progression by targeting microglia

2025-06-24

Hannah D. Mason , Yvonne L. Latour , Christopher T. Boughter +7 more | Nature Immunology

Retinal Microglia: Revealing New Opportunities for Identifying Early Biomarkers of Diabetic Retinopathy

2025-06-24

Ohisa Harley , Yufilia Suci Amelia , Elsa Gustianty +2 more | Current Eye Research

To explore the role of microglia in the pathomechanism of diabetic retinopathy (DR) from an inflammatory perspective.Methods: The study was conducted by searching several databases. Relevant articles were collected, summarized, … To explore the role of microglia in the pathomechanism of diabetic retinopathy (DR) from an inflammatory perspective.Methods: The study was conducted by searching several databases. Relevant articles were collected, summarized, and concluded. Numerous studies have been conducted to identify inflammatory biomarkers for effective detection of DR; however, the results have been inconsistent. Microglia, the resident immune cells of the retinal tissue, are believed to play a potential role in the neuroinflammatory process induced by prolonged hyperglycemia in the retina. The excessive release of extracellular adenosine triphosphate (eATP) due to hyperglycemia may overstimulate P2X7R receptors, thereby activating the NLRP3 inflammasome, and leading to chronic progressive inflammation. Microglial activation and polarization may induce meta-inflammation, contributing to increased permeability and neovascularization, which in turn lead to proliferative diabetic retinopathy. Understanding this mechanism is essential for identifying potential biomarkers for early DR detection and developing adjunctive therapies to control disease progression.

Microglial Dysfunction Mediated by Pb and Amyloid Beta Peptides as a Possible Mechanism of Neurotoxicity

2025-06-24

Lokesh Murumulla , Lakshmi Jaya Madhuri Bandaru , Rajanna Ajumeera +2 more | Journal of Applied Toxicology

ABSTRACT This study delves into the inflammatory and degenerative impacts of lead (Pb) toxicity and amyloid beta peptides (Aβ‐peptide 1–40 and Aβ‐peptide 25–35) on brain cells, particularly by fostering M1 … ABSTRACT This study delves into the inflammatory and degenerative impacts of lead (Pb) toxicity and amyloid beta peptides (Aβ‐peptide 1–40 and Aβ‐peptide 25–35) on brain cells, particularly by fostering M1 polarization in microglial cells and subsequent neuronal cell death, crucial in conditions like Alzheimer's disease. Microglia were exposed to IC 50 concentrations of Pb, and Aβ‐peptide 1–40 and Aβ‐peptide 25–35 exhibited notable increases in intracellular ROS levels (32.95%) upon exposure to combinatorial treatments. Moreover, there was a significant decline in total antioxidant capacity to 69.57%, suggesting oxidative damage and compromised cellular defenses against stress, coupled with heightened glutamate levels (921.3 μM). Treatment with Pb alongside Aβ‐peptide 1–40 and Aβ‐peptide 25–35 also led to elevated intracellular calcium levels (33.83%) and increased production of pro‐inflammatory cytokines IL‐6 (5.54 pg/mL), TNF‐α (5.8 pg/mL), and IFN‐γ (13.52 pg/mL) and reduced levels of anti‐inflammatory cytokines IL‐10 (5.61 pg/mL) and IL‐4 (14.46 pg/mL) in microglial cells compared with the control group. Furthermore, upregulation of NF‐κB/p65 pathway‐associated markers was observed, and when co‐cultured with neuronal cells for 24 h, polarized microglia induced neuronal cell death (57.9%). These findings provide insights into the complex molecular mechanisms involved in lead‐induced neurotoxicity and neurodegenerative disorders.

Temporal Dynamics of APOE and TREM2 Expression in Microglial Activation of NMOSD Mouse Models

2025-06-23

Si Xu , Wentao Dai , Tianfeng Wang +5 more | Molecular Neurobiology

The APOE–Microglia Axis in Alzheimer’s Disease: Functional Divergence and Therapeutic Perspectives—A Narrative Review

2025-06-23

Amy Liu , Tingyue Wang , Yang Liu +1 more | Brain Sciences

Apolipoprotein E (APOE) alleles play distinct roles in the pathogenesis of Alzheimer’s disease (AD), with APOEε4 being the strongest genetic risk factor for late-onset AD, while APOEε2 appears protective. Despite … Apolipoprotein E (APOE) alleles play distinct roles in the pathogenesis of Alzheimer’s disease (AD), with APOEε4 being the strongest genetic risk factor for late-onset AD, while APOEε2 appears protective. Despite extensive research, the precise mechanisms by which APOE alleles contribute to AD pathology remain incompletely understood. Recent advances in multi-omics technologies and single-cell analyses have revealed that APOE alleles shape microglial phenotypes, thereby affecting amyloid clearance, inflammatory responses, tau pathology, and lipid metabolism. In this review, we provide a detailed overview of how APOE alleles differentially regulate microglial activation, inflammatory signaling, phagocytic activity, and lipid metabolism in the context of AD, with a particular focus on the APOEε4-mediated disruption of microglial homeostasis via pathways such as TREM2 signaling, NF-κB/NLRP3 activation, ACSL1 upregulation, and HIF-1α induction. These insights not only advance our understanding of APOE allele-specific contributions to AD pathology, but also highlight novel therapeutic strategies targeting the APOE–microglia axis.

A Comprehensive Review of the Role of the Microbiota–Gut–Brain Axis via Neuroinflammation: Advances and Therapeutic Implications for Ischemic Stroke

2025-06-23

Hui Guo , Xiang Tang , Xinyi He +4 more | Biomolecules

The human gastrointestinal tract harbors a complex and diverse microbial community. Emerging evidence has revealed bidirectional communication between the gut microbiome and the central nervous system, termed the “microbiota–gut–brain axis”. … The human gastrointestinal tract harbors a complex and diverse microbial community. Emerging evidence has revealed bidirectional communication between the gut microbiome and the central nervous system, termed the “microbiota–gut–brain axis”. This axis serves as a critical regulator of glial cell function, positioning it as an essential target for ameliorating the onset and progression of ischemic stroke. In this review, we discuss the developments in the relationship between ischemic stroke and neuroinflammation via MGBA. The gut microbiome plays a critical role in signaling to microglia, astrocytes, and other immune components within this axis. We also summarize the interactions between the gut microbiota and glial cells under both healthy and ischemic stroke conditions. Additionally, we also focus on the role of microbiota-derived metabolites and neurotransmitters in ischemic stroke. Furthermore, we investigate the potential of targeting the intestinal and blood–brain barriers to improve MGBA. Finally, we evaluate the preclinical and clinical evidence for dietary interventions, probiotics, prebiotics, and fecal microbiota transplantation in ischemic stroke. A comprehensive understanding of the MGBA is essential for developing MGBA-based treatment for ischemic stroke.

Early abstinence in severe alcohol use disorder: MCP-1 decline, choroid plexus shrinkage, and region-specific grey-matter volume changes

2025-06-23

Géraldine Petit , Selim Mohamed Kotb , Santiago Canals +5 more | Research Square (Research Square)

<title>Abstract</title> In this longitudinal study, 37 patients with severe alcohol use disorder (SAUD) were tested at the beginning (T1) and end (T2) of withdrawal to explore the evolution of and … <title>Abstract</title> In this longitudinal study, 37 patients with severe alcohol use disorder (SAUD) were tested at the beginning (T1) and end (T2) of withdrawal to explore the evolution of and relationship between systemic inflammation, volumetric changes for brain grey matter (GM) and choroid plexus (ChP), and clinical symptoms. At T1, patients exhibited high levels of anxiety, depression, and craving, and had elevated plasmatic pro-inflammatory cytokines, indicating low-grade systemic inflammation. MCP-1 levels correlated positively with ChP volume and severity of withdrawal symptoms, while MIP-1β also correlated with ChP volume, together suggesting an acute immune response at T1, and underscoring the ChP as a potential neuroimmune biomarker. During three weeks’ abstinence, IL-8, MIP-1β, and MCP-1 levels decreased, although MIP-1β did not return to control levels, and TNF-α showed no significant reduction. Volumetric MRI analyses suggested two concurrent trajectories during withdrawal. First, an overall “recovery‐driven” pattern of rapidly increasing grey matter (GM) volume in widespread forebrain regions with parallel declines in ventricle size and craving. Second, GM in limbic cortical areas, temporal and inferior frontal cortex showed no significant volumetric gain. However, these regional volumes correlated significantly with declining MCP‐1, indicative of a “deflation”, potentially related to declining microglial activation. These findings highlight the role of inflammatory processes in shaping early neuroplastic changes during withdrawal and point to a central role of MCP‐1 in inflammation-driven morphometric changes.

Astragaloside’s Role in Microglial Neuroinflammation: A Multi-Method Study Combining Experimental and Computational Analyses

2025-06-23

Dian Ou , Jiating Li , Yi‐Ming Shi +7 more | Neurochemical Research

Impact of Gut Microbiota Alterations on Mitochondrial Bioenergetics in Cortical Astrocytes and Sensorimotor Impairment in a Rat Model of Lipopolysaccharide-Associated Encephalopathy

2025-06-23

Chun‐Ta Huang , Ying-Chou Wang , Shih-Chang Lin +4 more | Shock

Brain dysfunction is a significant complication of sepsis, commonly referred to as sepsis-associated encephalopathy (SAE). Alterations in gut microbiota during sepsis may contribute to development of SAE through the gut-brain … Brain dysfunction is a significant complication of sepsis, commonly referred to as sepsis-associated encephalopathy (SAE). Alterations in gut microbiota during sepsis may contribute to development of SAE through the gut-brain axis. This study investigated effects of fecal transplantation from healthy or endotoxemic individuals on gut microbiota and brain function in a rat model of lipopolysaccharide (LPS)-associated encephalopathy. Following LPS induction, rats received daily oral gavage of fecal microbiota transplants for three days. Sensory and motor functions were assessed daily throughout the seven-day study period after LPS exposure. On day seven post-LPS, the study examined gut microbiota structure and composition, serum and fecal short-chain fatty acids (SCFAs) levels, ileal villus length, intestinal permeability, neuronal and glial ultrastructure, cytokine concentrations (pro-inflammatory and anti-inflammatory), and mitochondrial bioenergetics. Administration of healthy donor feces preserved gut microbial structure and composition, maintained ileal villus length, and improved intestinal permeability following LPS treatment. Additionally, it increased SCFA levels, reduced pro-inflammatory cytokines, enhanced anti-inflammatory cytokine release, and restored sensitivity to mechanical and thermal stimuli, as well as motor function. Rats treated with healthy donor feces also exhibited reduced neuronal necrosis and a decreased density of mitochondria in cortical astrocytes. Notably, mitochondrial metabolism in LPS-treated rats returned to near-normal levels following treatment with healthy donor feces. In contrast, administration of endotoxemic donor feces exacerbated these effects in LPS-treated rats. Ameliorating gut dysbiosis prevents mitochondrial dysfunction in astrocytes by promoting SCFA production and enhancing anti-inflammatory cytokine release. This process preserves neuronal integrity and mitigates the severity of encephalopathy.

Distinct composition of different types of Abeta plaques in the pathogenesis of Alzheimer’s disease and the role of neutrophil-derived myeloperoxidase

2025-06-22

Jianru Sun , Xiangqi Shao , Xue Wang +6 more | Molecular Brain

Abstract Alzheimer’s disease (AD) is an age-related neurodegenerative disorder. Different types of Aβ plaques are likely to play distinct roles in the brains of patients with AD. In this study, … Abstract Alzheimer’s disease (AD) is an age-related neurodegenerative disorder. Different types of Aβ plaques are likely to play distinct roles in the brains of patients with AD. In this study, through the combination of pathological techniques and analysis of the human brain database, we discovered that focal Aβ plaques (FAPs), rather than diffuse Aβ plaques (DAPs), are significantly correlated with AD-related neuropathological changes and cognitive impairment. By using laser capture microdissection in conjunction with microproteomics, the protein components of different Aβ plaques were characterized. Bioinformatic analysis indicated that FAP-enriched proteins are associated mainly with immune-related pathways, such as neutrophil extracellular trap formation. We further confirmed that myeloperoxidase (MPO) is significantly upregulated in the AD brain and colocalizes with FAPs but not with DAPs. Immunohistochemical staining demonstrated that neutrophils expressing MPO accumulated in the capillary lumen and brain parenchyma. The number of neutrophils significantly increases in the cortex and hippocampus of AD donors. Our study revealed a potential role for neutrophil-derived MPO in FAPs, providing insights into the pathogenesis mechanisms and potential therapeutic targets of AD.

Autoantibodies in Alzheimer's disease: Multifaceted roles and therapeutic horizons

2025-06-22

Jin Gong , Shaoqi Li , Xiaodong Han +7 more | Journal of Alzheimer s Disease

Background Alzheimer's disease (AD) is a neurodegenerative disorder characterized by pathogenesis involving numerous factors. Recent research has highlighted the significant role of autoimmunity in the initiation and progression of AD, … Background Alzheimer's disease (AD) is a neurodegenerative disorder characterized by pathogenesis involving numerous factors. Recent research has highlighted the significant role of autoimmunity in the initiation and progression of AD, with autoantibodies emerging as a pivotal area of investigation. Nevertheless, the influence of autoantibodies in AD is marked by substantial heterogeneity, they may either mitigate disease progression by clearing pathogenic protein aggregates or exacerbate the pathological process through mechanisms such as the activation of inflammatory responses or the induction of neuronal damage. Objective This review aims to synthesize the various roles of autoantibodies in AD, examine the factors that influence their functions, and assess their potential application in precision immunotherapy. Methods PubMed and Web of Science databases were searched for English-language papers (2015–2025). Peer-reviewed human, animal and cell studies, systematic reviews and meta-analyses were screened independently by two reviewers. Results A total of 87 studies were selected for inclusion, spanning human, animal, and cellular research. The findings indicated that certain autoantibodies, such as those targeting amyloid-β, tau, or 4-hydroxynonenal, may confer neuroprotective effects. Conversely, other autoantibodies, including those against BACE1, aquaporin-4, or HuD, may exacerbate AD pathology. Importantly, some autoantibodies were found to exhibit dual roles, contingent upon their specific modifications or the context of the disease. Conclusions Autoantibodies constitute a double-edged immune axis in AD. Their impact hinges on antigen class, disease stage, isotype affinity and glycosylation. Precision strategies—like CAAR-T cell therapy, glycosylation modulation, and affinity optimization—offer therapeutic promise but require further validation.

Lipocalin-2 regulates astrocyte-oligodendrocyte interaction to drive post-stroke secondary demyelination

2025-06-21

Zhenqian Huang , Xiaohao Zhang , Ying Zhao +7 more | Cell Reports

Ligand–Receptor Analysis of Brain Cell Type Marker Data Reveals Intricate Endothelial Interaction

2025-06-21

Anoop Kumar Mishra , G. S. Naveen Kumar | Annals of Neurosciences

Brain endothelial interaction with neurons, astrocytes, oligodendrocytes and microglial cells is critical for brain physiology; it is still far from being mapped. Understanding of the endothelial communication with other brain … Brain endothelial interaction with neurons, astrocytes, oligodendrocytes and microglial cells is critical for brain physiology; it is still far from being mapped. Understanding of the endothelial communication with other brain cell type could unravel novel insight into neurovascular homeostasis. This study aims to construct neurovascular interaction network, focusing on brain endothelial cell interactome using brain cell marker gene dataset and ligand-receptor (LR) pair. We curated brain marker gene list from McKenzie et al.'s brain cell type top 1000 marker list of endothelial, microglia, astrocyte, neuron, oligodendrocyte and oligodendrocyte progenitor cell (OPC) and extracted LR interaction between them. Subsequently, using Cytoscape, endothelial cell interaction map was constructed and top interaction and hub gene were derived. Moreover, we performed Kyoto encyclopedia of genes and genomes (KEGG) pathways enrichment (p value < .1) to infer biological information hidden. Neurovascular LR interaction showed endothelial cells as the top network having 25.34% of total interaction with 176 outgoing and 171 incoming interactions. A considerable portion of signalling (11%) is involved in autocrine signalling functionally related to vascular tone, angiogenesis and others. Paracrine signalling between endothelial cells with microglia, astrocytes, neurons and OPC constituted 13.5%, 8.9%, 5.8% and 4.9% of total interactions, respectively. Functional enrichment of LR interaction in endothelial-microglia, endothelial-astrocyte and endothelial-neuron networks constitutes 49, 45 and 36 significant KEGG pathways (p value < .1) respectively. These pathways include extracellular matrix (ECM) receptor, axon guidance, chemokine, nuclear factor kappa B (NF-kB) and signalling pathways, among others. Hub gene analysis showed ITGB1 in endothelial cells, ITGA4 in microglia, NOTCH2 in astrocytes and LAMC2 in neurons having maximum interaction in the endothelial network. This study recapitulated not only previously known gene interactions using a markers gene list but also identified novel interactions between endothelial and other brain cell types. In conclusion, this analysis underscores the critical role of endothelial cell interactions in brain physiology.

Sanggenol L inhibits the HMGB1/TLR4/NF-κB signaling pathway to prevent cerebral ischemia-reperfusion damage

2025-06-21

Xuehui Mao , Xuefang Jing , Siyi Liu +4 more | Journal of Molecular Histology

Network pharmacology-based prediction and “gut microbiota-inflammation-brain axis” validation of the active ingredients and potential mechanisms of Plantagins Herba for treating diabetes-related cognitive dysfunction

2025-06-20

Zhixuan Huang , Jian Li , Hui Li +2 more | Frontiers in Pharmacology

Background Diabetes-related cognitive dysfunction (DRCD) is increasingly recognized as a common complication. However, there are currently no specific remedies for DRCD. Plantagins Herba contains many active ingredients that can regulate … Background Diabetes-related cognitive dysfunction (DRCD) is increasingly recognized as a common complication. However, there are currently no specific remedies for DRCD. Plantagins Herba contains many active ingredients that can regulate blood lipids and blood glucose. It is used to treat cognitive impairment, but its therapeutic effects and molecular mechanisms on DRCD have not been reported. Purpose To study the bioactive components, potential targets and molecular mechanisms of Plantagins Herba in the treatment of DRCD. Methods Network pharmacology was applied to predict the active component of Plantagins Herba and the therapeutic targets of diabetes-related cognitive impairment. The molecular docking of the core components with the key targets was verified. Cell and animal models were established, and the mechanism by which hispidulin treats DRCD was explored via flow cytometry, Western blotting, behavioral experiments, HE staining, immunofluorescence, 16S rRNA and other techniques. Results Based on the network pharmacology analysis, hispidulin derived from Plantaginis Herba was identified as a promising candidate for further investigation. The computational predictions suggest that the MAPK and PI3K/AKT signaling pathways may play pivotal roles in DRCD pathogenesis. In vitro , Hispidulin reduced inflammation and apoptosis in BV2 cells. It also improved the viability of HT22 cells under inflammation conditions and increased the expression levels of β-catenin and Cyclin D1 proteins. In vivo , hispidulin significantly reduced glucose and lipid metabolism disorders and the abundance of harmful flora in diabetic mice with cognitive impairment. The immunofluorescence results suggested that hispidulin reduced the activation of microglia in the mouse brain and decreased inflammation. The expression of p38MAPK/PI3K/AKT signaling pathway and β-catenin, Cyclin D1 protein, which confirmed regulatory effect of Hispidulin in hippocampal tissue. Conclusion Hispidulin ameliorated disease manifestations in a DRCD-induced murine model, attenuating neuroinflammation and histopathological damage in hippocampal tissues through gut microbiota modulation.

Modeling neuroinflammatory interactions between microglia and astrocytes in a human iPSC-based coculture platform

2025-06-20

Iisa Tujula , Tanja Hyvärinen , Johanna Lotila +7 more | Cell Communication and Signaling

Abstract Background Microglia and astrocytes are central mediators of neuroinflammation in several neurodegenerative diseases. Their intricate crosstalk and contributions to pathogenesis remain elusive, highlighting the need for innovative in vitro … Abstract Background Microglia and astrocytes are central mediators of neuroinflammation in several neurodegenerative diseases. Their intricate crosstalk and contributions to pathogenesis remain elusive, highlighting the need for innovative in vitro approaches for investigating glial interactions in neuroinflammation. This study aimed to develop advanced human-based glial coculture models to explore the inflammatory interactions of microglia and astrocytes in vitro. Methods Human induced pluripotent stem cell (iPSC)-derived microglia and astrocytes were cultured both in conventional culture dishes and in a microfluidic coculture platform. This platform features separate compartments for both cell types, enabling the creation of distinct microenvironments with spontaneous migration of microglia toward astrocytes through interconnecting microtunnels. To induce inflammatory activation, glial cultures were stimulated with lipopolysaccharide (LPS), a combination of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), or interferon-γ (IFN-γ) for 24 h. Glial activation and interactions were analyzed with immunocytochemistry, the secretion of inflammatory factors from the culture media was measured, and microglial migration was quantified. Results Microglia–astrocyte cocultures were generated in both conventional cultures and the microfluidic platform. Inflammatory stimulation with LPS and TNF-α/IL-1β elicited cell type-specific responses in microglia and astrocytes, respectively. LPS stimulation of cocultures induced lower secretion of several inflammatory mediators, suggesting dampening of microglial inflammatory responses when cocultured with astrocytes. Notably, inflammatory interaction between glial cells was demonstrated by increased level of IL-10 after TNF-α/IL-1β stimulation in cocultures compared with monocultures. The microfluidic coculture platform enabled the parallel study of microglial migration, glial activation and phagocytic function, thereby facilitating the investigation of glial responses within distinct inflammatory microenvironments. Furthermore, glial inflammatory responses and interactions were demonstrated in the controlled microenvironments of the microfluidic coculture platform. The inflammatory coculture environment was associated with elevated levels of complement component C3, emphasizing the intricate interplay between microglia and astrocytes. Conclusions Our results depict an elaborate inflammatory interaction between iPSC-derived microglia and astrocytes via reciprocal molecular signaling. Importantly, the microfluidic coculture platform established in this study provides a more functional and advanced setup for investigating inflammatory glial interactions in vitro.

Targeting microglial PPARα ameliorates the outcome of ischemic stroke by enhancing interaction with infiltrating peripheral monocytes/macrophages

2025-06-20

Tong Ren , Maoshu Zhu , Xilin Jiang +7 more | Cell Reports

The SARS-CoV-2 nucleocapsid protein induces microglia senescence- mediated cognitive impairment via glycolysis

2025-06-20

Nan‐Shi‐Yu Yang , Han-Xi Sha , Chenyu Zhang +7 more | Research Square (Research Square)

<title>Abstract</title> COVID-19-associated cognitive dysfunction has emerged as a significant public health challenge, creating substantial socioeconomic burdens for affected individuals, their families, and healthcare systems. Our study found that the SARS-CoV-2 … <title>Abstract</title> COVID-19-associated cognitive dysfunction has emerged as a significant public health challenge, creating substantial socioeconomic burdens for affected individuals, their families, and healthcare systems. Our study found that the SARS-CoV-2 nucleocapsid protein (SARS-CoV-2 N protein), the fundamental architectural element of viral particles, as a novel molecular driver of neurocognitive impairment. We observed that N protein caused microglial senescence both <italic>in vivo</italic> and <italic>in vitro</italic>. Mechanistically, N protein-induced metabolic shifting toward glycolysis initiates a cascade of microglial senescence that propagates cognitive impairment. We found that glycolysis inhibition inhibited N protein-triggered microglial senescence and attenuated cognitive impairment in mice. Disrupted mitochondrial dynamics impair oxidative phosphorylation capacity, forcing glycolytic reprogramming that ultimately triggers cellular senescence activation. We found that the N protein promotes excessive mitochondrial dysfunction in microglia, resulting in mitochondrial fragmentation. Inhibition of mitochondrial fission effectively rescued N protein-induced microglial senescence in microglia. In conclusion, our study suggests that the N protein induces senescence-mediated cognitive impairment by promoting glycolysis in microglia. Therapeutic targeting of glycolysis in N protein-triggered microglial senescence could be beneficial for treating or preventing cognitive impairment.

Human induced neural progenitor cells generated from three-dimensional aggregate-based culture significantly improve post-stroke recovery in tMCAO mice

2025-06-20

Zeqin Fu , Yue Hu , Yuxia Wang +7 more | Stem Cell Research & Therapy

Despite the high prevalence of cerebral ischemic stroke, effective clinical treatments remain limited. With the development of regenerative medicine, induced neural progenitor cells (iNPCs) demonstrate ideal potential and good availability … Despite the high prevalence of cerebral ischemic stroke, effective clinical treatments remain limited. With the development of regenerative medicine, induced neural progenitor cells (iNPCs) demonstrate ideal potential and good availability for autologous transplantation therapy. However, current differentiation protocols for iNPCs still have room for improvement in terms of purity, reproducibility, scalability and differentiation potential. We aimed to develop a scalable, stable, and efficient 3D aggregate-based method for iNPC production in suspension culture, avoiding detrimental cell dissociation and replating processes. We evaluated the therapeutic potential of iNPCs in the chronic phase of a transient middle cerebral artery occlusion (tMCAO) mouse model and explored iNPC subpopulations via single-cell RNA sequencing to elucidate their pleiotropic therapeutic potentials. iNPCs generated from three iPSC lines displayed high NPC marker expression and an average 176-fold cell expansion over the 12-day culture period. These iNPCs could spontaneously differentiate into both neurons and glial cells in vitro. In the tMCAO model, transplanted iNPCs remodeled the microenvironment by alleviating neuroinflammation, inhibiting chronic microgliosis and astrogliosis, promoting M2 polarization of microglia, and preserving astrocytic morphology in the ischemic penumbra. Mechanistically, iNPCs can be divided into four subpopulations, with neuroepithelia being the most abundant and capable of rapidly replenishing damaged cells and mitigating microenvironmental deterioration. We developed a simple and efficient 3D aggregate-based method for iNPC differentiation. These iNPCs showed excellent potential for post-stroke recovery and represent a valuable tool for clinical translation.

Isolation and Flow Cytometric Assessment of Neuroimmune Interactions in a Mini-Stroke Murine Model

2025-06-20

Song Wang , Jingyi Yao , Yitong Du +5 more | Journal of Visualized Experiments

Delphinidin attenuates cognitive deficits and pathology of Alzheimer’s disease by preventing microglial senescence via AMPK/SIRT1 pathway

2025-06-20

Ying Liu , Ting Hong , Mingxuan Lv +4 more | Alzheimer s Research & Therapy

Emerging evidence suggests that senescent microglia play a role in β-amyloid (Aβ) pathology and neuroinflammation in Alzheimer's disease (AD). Targeting senescent cells with naturally derived compounds exhibiting minimal cytotoxicity represents … Emerging evidence suggests that senescent microglia play a role in β-amyloid (Aβ) pathology and neuroinflammation in Alzheimer's disease (AD). Targeting senescent cells with naturally derived compounds exhibiting minimal cytotoxicity represents a promising therapeutic strategy. This study aimed to investigate whether delphinidin, a naturally occurring anthocyanin, can alleviate AD-related pathologies by mitigating microglial senescence and to elucidate the underlying molecular mechanisms. We employed APP/PS1 mice, naturally aged mice, and an in vitro model using Aβ42-induced senescent BV2 microglia. Delphinidin's effects were evaluated through assessments of cognitive function, synaptic integrity (synapse loss), Aβ plaque burden, senescent microglia gene signatures, and cellular senescence markers (including senescence-associated β-galactosidase activity, SASP factor expression, oxidative stress, and cyclin p21/p16 levels). Mechanistic studies involved analyzing the AMPK/SIRT1 signaling pathway, testing direct delphinidin-SIRT1 interaction, and using the AMPK inhibitor Compound C. Delphinidin treatment significantly alleviated cognitive deficits, synapse loss, Aβ peptides plaques of APP/PS1 mice via downregulated senescent microglia gene signature, prevented cell senescence, including senescence-associated β-galactosidase activity, senescence-associated secretory phenotype (SASP), oxidative stress, cyclin p21 and p16. And delphinidin treatment also prevented microglial senescence in naturally aged mice. In vitro, delphinidin treatment attenuated cell senescence induced by Aβ42 in BV2 microglia cells. Further research indicated that delphinidin treatment enhanced the AMPK/SIRT1 signaling pathway. Additionally, delphinidin was found to directly interact with SIRT1. It's noteworthy that AMPK inhibitor Compound C inversed the protective effect of delphinidin against microglial senescence. Our study reveals for the first time that delphinidin effectively improved cognitive deficits, alleviated synapse loss and Aβ pathology in APP/PS1 mice by mitigating microglial senescence. These findings highlight delphinidin as a promising natural anti-aging agent against the development of aging and age-related diseases.

Adaptive immunity in the pathogenesis and treatments of Parkinson’s disease

2025-06-20

Xiaoqing Du , Sharmin Akter , Davina B. Oludipe +4 more | NeuroImmune Pharmacology and Therapeutics

Abstract Neuroimmunity drives the pathophysiology of Parkinson’s disease (PD). This disease affects both the central and peripheral nervous systems. The immune system is engaged through the progressive accumulation of alpha-synuclein … Abstract Neuroimmunity drives the pathophysiology of Parkinson’s disease (PD). This disease affects both the central and peripheral nervous systems. The immune system is engaged through the progressive accumulation of alpha-synuclein (α-syn), a driver of immunity and a pathological hallmark of PD. Consequent α-syn-induced immune activation leads to neuronal damage. This leads not only to the activation of microglia within the central nervous system, but also to the recruitment and activation of peripheral immune cells that infiltrate the brain and contribute to a widespread immune response. Moreover, PD-associated genes and risk factors have been increasingly recognized as essential regulators of immune functions. This review summarizes the current understanding of adaptive immunity in PD and explores emerging immunomodulatory strategies that may inform future therapeutic development.

Key immune regulators in retinal ischemia-reperfusion injury via RNA sequencing

2025-06-20

Shan He , Changhong Ren , Tingting Meng +2 more | International Journal of Ophthalmology

AIM: To explore the immune cell infiltration and molecular mechanisms of retinal ischemia-reperfusion injury (RIRI) to identify potential therapeutic targets. METHODS: In the bulk RNA-seq analysis, This study performed differential … AIM: To explore the immune cell infiltration and molecular mechanisms of retinal ischemia-reperfusion injury (RIRI) to identify potential therapeutic targets. METHODS: In the bulk RNA-seq analysis, This study performed differential gene expression analysis, weighted gene co-expression network analysis, and protein-protein interaction network analysis to identify hub genes. QuanTIseq was used to determine the composition of infiltrating immune cells. Following the identification of hub genes, single-cell RNA-seq analysis was employed to pinpoint the specific immune cell types expressing these hub genes. Cell-cell communication analysis to explore signaling pathways and interactions between immune cells was further performed. Finally, the expression of these key immune regulators in vivo using quantitative real-time polymerase chain reaction (qRT-PCR) was validated. RESULTS: Bulk RNA-seq analysis identified Stat2, Irf7, Irgm1, Igtp, Parp9, Irgm2, Nlrc5, and Tap1 as hub genes, with strong correlations to immune cell infiltration. Single-cell RNA-seq analysis further revealed six immune cell clusters, showing Irf7 predominantly in microglia and Tap1 in dendritic cells (DCs). And cell-cell communication analysis showed that microglia and DCs play central roles in coordinating immune activity. qRT-PCR validated the upregulation of these genes. CONCLUSION: In the acute phase of RIRI, Irf7 and Tap1 may be the potential therapeutic targets to reduce inflammation and promote neurological function recovery.

Regulation of L-Lactate in Glutamate Excitotoxicity Under Cerebral Ischemia: Pathophysiology and Preventive Strategy

2025-06-20

Mao Zhang , Yanyan Wang , Zili Gong +3 more | Pharmaceuticals

Glutamate is an excitatory neurotransmitter in the central nervous system (CNS) that mediates synaptic transmission. However, glutamate homeostasis among neural cells is broken in cerebral ischemia. Excessive glutamate triggers N-methyl-d-aspartate … Glutamate is an excitatory neurotransmitter in the central nervous system (CNS) that mediates synaptic transmission. However, glutamate homeostasis among neural cells is broken in cerebral ischemia. Excessive glutamate triggers N-methyl-d-aspartate receptors (NMDARs) in postsynaptic neurons, leading to intracellular calcium (Ca2+) overload and excitoneurotoxicity. At this moment, L-lactate may affect NMDARs and play a protective role in cerebral ischemia. This work proposes that L-lactate regulates glutamate signaling among neural cells. But, dysregulation of L-lactate in glutamate signaling cascades contributes to glutamate excitotoxicity in cerebral ischemia. In detail, L-lactate regulates the glutamine(Gln)-glutamate cycle between astrocytes and presynaptic neurons, which triggers the astroglial L-lactate-sensitive receptor (LLR)-cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway, coordinating astroglial glutamate uptake and neuronal glutamate transmission. L-lactate mediates glutamate signaling and synaptic transmission among neural cells. In addition, L-lactate promotes the function of mitochondrial calcium uniporter complex (MCUC), which quickly depletes intracellular Ca2+ in postsynaptic neurons. In addition, L-lactate can promote the conversion of microglia from the pro-inflammatory (M1) to anti-inflammatory (M2) phenotype. Therefore, regulation of L-lactate in glutamate signaling in the CNS might become a preventive target for cerebral ischemia.

Age‐Related Complement <scp>C3</scp> Drives Memory Impairments and Associated Neuropathologies in a Mouse Model

2025-06-20

Miaomiao Du , Yujia Wang , Xinyuan Wang +7 more | Aging Cell

ABSTRACT Aging is the greatest risk factor for learning and memory disorders; dementia prevalence significantly increases with age due to numerous molecular changes in the body. Although research has consistently … ABSTRACT Aging is the greatest risk factor for learning and memory disorders; dementia prevalence significantly increases with age due to numerous molecular changes in the body. Although research has consistently shown that aging leads to learning and memory impairments, the molecular mechanisms linking aging to these cognitive deficits remain incompletely understood. Previous studies have revealed that complement C3 levels increase with age in humans, monkeys, and mice; elevated C3 expression is also observed in the brains of dementia patients. These data suggest that C3 plays critical roles in initiating learning and memory impairments. To investigate whether C3 contributes to these deficits during aging, we developed a transgenic mouse model with elevated C3 expression to simulate age‐related increases. Mice with increased C3 expression showed impaired learning and memory, along with synaptic loss, neuronal loss, and astrocytosis. Quantitative polymerase chain reaction microarray and cellular assays revealed that C3 elevation may impair cognitive functions by affecting insulin signaling pathways. Notably, antibody therapy targeting complement C3 in SAMP8 mice, which naturally exhibit increased brain C3 levels, alleviated their learning and memory deficits. These findings suggest that age‐related complement C3 elevation drives memory impairments and associated neuropathologies; targeting complement C3 may alleviate these deficits.

Role of BDNF Expression Through Microglial Polarization in Adult Hippocampal Neurogenesis in Depression and the Therapeutics

2025-06-20

Sheng Gao | Theoretical and Natural Science

The present study tests the proposition that enhancement of BDNF by polarizing microglial cells from M1 to M2 contribute to the phenomenon of hippocampal neurogenesis and synaptic plasticity, thus reducing … The present study tests the proposition that enhancement of BDNF by polarizing microglial cells from M1 to M2 contribute to the phenomenon of hippocampal neurogenesis and synaptic plasticity, thus reducing depressive-like behaviors. The experimental design covers both in vitro and in vivo, with BACE1-modified microglial culture, co-culture with neural progenitors, and a mouse model of depressed state. Thus, the present study intends to understand exactly how microglial polarization is connected to the alteration in BDNF and adult hippocampal neurogenesis in depression. It is possible that the results obtained will shed light on the new therapeutic approaches to influencing microglial polarization and BDNF receptor expression in depressive disorders and improving the efficacy of the therapies. The present study adds to the current knowledge about the neuroinflammation process in psychiatric diseases, as well as possibly offering hope for better biology-driven treatment options for depression in the future.

GIT 27 Modulates TLR4/Src/NOX2 Signaling Pathway: A Potential Therapeutic Strategy to decrease Neuroinflammation, Oxidative Stress and Neuronal Cell Death in Parkinson’s Disease

2025-06-20

Alessio Ardizzone , Laura Cucinotta , Giovanna Casili +5 more | Free Radical Biology and Medicine

Agomelatine improves the cognitive function of rats with traumatic brain injury by regulating the polarization of microglia in the hippocampus

2025-06-20

Lin Yongshuang , Wei Shiyin , Shao Binbin +2 more | Research Square (Research Square)

<title>Abstract</title> <bold>Objective</bold>: To explore the effect and mechanism analysis of agomelatine (AGO) in improving cognitive impairment in rats with traumatic brain injury (TBI). <bold>Methods</bold>: Thirty rats were divided into the … <title>Abstract</title> <bold>Objective</bold>: To explore the effect and mechanism analysis of agomelatine (AGO) in improving cognitive impairment in rats with traumatic brain injury (TBI). <bold>Methods</bold>: Thirty rats were divided into the Sham group and the TBI group. The TBI group established the TBI rat model by free fall strike. After AGO intervention was conducted on 10 randomly selected rats, the cognitive levels of rats in each group were detected by Morris water maze and field experiments. <bold>Result</bold>: The protein expressions of TLR4, MyD88 and NF-κB increased, and the expression level of NF-κB in hippocampal tissue also increased (P < 0.05). <bold>Conclusion</bold>: AGO improves cognitive dysfunction in TBI rats, which may be related to its promotion of M2 polarization of hippocampal microglia, thereby reducing inflammatory injury and inhibiting the TLR4/MyD88/NF-κB pathway.

Frequency of synaptic antigen-specific CD4+ T cells in dementia is age-dependent but not correlated with cognitive impairment

2025-06-19

Julius Hoffmann , Marie-Luise Machule , Jakob Kreye +7 more | Immunity & Ageing

Abstract Neurodegenerative dementias including Alzheimer disease severely impair cognitive and social abilities and are a major cause of mortality with no causal treatment yet. Autoimmune mechanisms have been increasingly considered … Abstract Neurodegenerative dementias including Alzheimer disease severely impair cognitive and social abilities and are a major cause of mortality with no causal treatment yet. Autoimmune mechanisms have been increasingly considered to contribute to disease progression, e.g. by enhancing protein misfolding or pro-inflammatory immune responses. Understanding this contribution may lead to novel treatment options beyond removing neurodegeneration-associated proteins. We hypothesized that CD4 + T H cells against synaptic proteins may play a role in dementia, given the profound changes of synaptic proteins in the disease. We investigated T H cell frequencies and phenotypes after antigen-reactive T cell enrichment (ARTE) using three important synaptic antigens known to play a role in cognitive function, N-Methyl-D-Aspartate receptor (NMDAR), Leucine-rich, glioma inactivated 1 (LGI1) and metabotropic glutamate receptor 5 (mGluR5). Our data revealed that synaptic autoantigen-specific T H cells occurred in all cohorts and were similarly frequent in patients with dementia and sex- and age-matched controls. However, they were significantly reduced compared to young healthy subjects, indicating strong age-related effects (‘immune senescence’). Compared to the ubiquitously available Candida albicans antigen, synaptic autoantigen-specific T H cell responses were strongly driven by IFNγ-producing T cells, expression of which markedly decreased with age. Patients with dementia had significantly less IL-17-producing synaptic autoantigen-specific T H cells than aged healthy controls. This first direct ex vivo quantitative and qualitative analysis of circulating T cells autoreactive to three synaptic autoantigens in dementia shows no correlation with cognitive impairment. It suggests that synaptic autoantigen-specific T H cells decline with age and are not a major driver of dementia development.

KChIP3 fosters neuroinflammation and synaptic dysfunction in the 5XFAD mouse model of Alzheimer’s disease

2025-06-19

Bolívar Arcos-Encarnación , Eladio Cortes-Flores , Isabel Barón-Mendoza +7 more | Journal of Neuroinflammation

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by β-amyloid (βA) accumulation, neuroinflammation, excessive synaptic pruning, and cognitive decline. Despite extensive research, effective treatments remain elusive. Here, we identify … Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by β-amyloid (βA) accumulation, neuroinflammation, excessive synaptic pruning, and cognitive decline. Despite extensive research, effective treatments remain elusive. Here, we identify potassium channel-interacting protein 3 (KChIP3) as a key driver of AD pathology using the 5XFAD mouse model. KChIP3 levels were significantly elevated in the hippocampus of 5XFAD mice, correlating with βA burden and neuroinflammation. This upregulation was triggered by inflammatory signaling via the NLRP3 inflammasome and Caspase-1 activation. Notably, genetic deletion of KChIP3 (5XFAD/KChIP3-/-) markedly reduced βA plaque deposition, pro-inflammatory cytokines, reactive gliosis, and expression of inflammation-related proteins (APO, CLU, MDK). Transcriptomic and proteomic analyses revealed restored synaptic markers (CD47, CD200, CACNB4, GDA) and a shift of the disease-associated microglial (DAM-1) phenotype. Mechanistically, we propose that KChIP3 amplifies AD pathology through two key mechanisms: (1) sustaining neuroinflammation by upregulating pro-inflammatory genes and (2) impairing synaptic integrity by repressing genes critical for neuronal function. Consistently, KChIP3 deletion enhanced dendritic complexity, synaptic plasticity, and cognitive performance in 5XFAD mice. These findings position KChIP3 as a potential therapeutic target for mitigating neuroinflammation and synaptic dysfunction in AD and highlight its potential as a biomarker for disease progression.

Transcriptomic bioinformatics analysis proposes a novel BCL2-MAPK14-TXN oxidative stress diagnostic model of sepsis and identifies TXN as an oxidative stress-related signature gene in sepsis

2025-06-19

Zhao Zou , Meiling Wu , Yuce Peng +1 more | International Immunopharmacology

The application of telmisartan in central nervous system disorders

2025-06-19

Wei Quan , Shui-Xian Zhang , Xu-Yang Zhang +4 more | Pharmacological Reports

Telmisartan, a well-established antihypertensive drug, has shown promising therapeutic potential for a variety of central nervous system (CNS) disorders. This review outlines the fundamental characteristics of telmisartan, focusing on its … Telmisartan, a well-established antihypertensive drug, has shown promising therapeutic potential for a variety of central nervous system (CNS) disorders. This review outlines the fundamental characteristics of telmisartan, focusing on its dual pharmacological effects as an angiotensin II type 1 receptor (AT1R) antagonist and a peroxisome proliferator-activated receptor (PPAR) γ activator. These mechanisms underpin its neuroprotective and anti-inflammatory effects, which are essential to its therapeutic benefits in CNS diseases. Telmisartan modulates key cellular components of the CNS, including microglia, astrocytes, oligodendrocytes, vascular endothelial cells, and neurons, thereby offering protection against neuroinflammation, oxidative stress, and neuronal damage. We summarize telmisartan's efficacy in addressing a range of neurological conditions, such as stroke, traumatic brain injury, dementia, Parkinson's disease, demyelinating diseases, psychiatric disorders, and gliomas. By targeting multiple pathways involved in these disorders, telmisartan demonstrates potential as both an adjunctive and standalone therapy. Its ability to attenuate neuroinflammation and promote cellular repair highlights its versatility in CNS disease management. This review underscores the potential of telmisartan as a valuable therapeutic option for CNS disorders, warranting continued exploration to optimize its clinical application.

Exercise improves depressive-like behavior in adolescent mice by regulating sphingosine and ceramide metabolism through microglial CerS1

2025-06-19

Naigang Li , Yuan Yao , Jingyi Du +7 more | Communications Biology

Given the unique onset period of adolescent depression, it is crucial to prioritize treatment modalities that are not only effective but also carry low side effects and promote overall health, … Given the unique onset period of adolescent depression, it is crucial to prioritize treatment modalities that are not only effective but also carry low side effects and promote overall health, with exercise emerging as a notable option. High-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) stand out as two prominent forms of exercise, proven to be beneficial in addressing a multitude of disorders. Microglia mediated neuroinflammation is one of the main hypotheses leading to depression. Neuroinflammation leads to abnormal synaptic function, impaired neuroplasticity, and ultimately depressive symptoms. However, the exact mechanisms of exercise in microglia and adolescent depression remain unclear. In this study, we found that exercise can increase the expression of microglial ceramide synthase 1 (CerS1), promote the synthesis of C18 ceramide from sphingosine, and improve depressive-like behaviors in adolescent mice. Overexpression of CerS1 in the CA1 region using microglia specific adeno-associated virus (AAV) inhibits chronic unpredictable mild stress (CUMS) induced neuroinflammation. Meanwhile, overexpression of CerS1 in primary microglia inhibits lipopolysaccharide (LPS) induced neuroinflammation. These results provide new theoretical support for the treatment of adolescent depression with exercise from the perspective of animal models.

TGFα controls checkpoints in CNS resident and infiltrating immune cells to promote resolution of inflammation

2025-06-19

Lena Lößlein , Mathias Linnerbauer , Finnja Zuber +7 more | Nature Communications

Abstract After acute lesions in the central nervous system (CNS), the interaction of microglia, astrocytes, and infiltrating immune cells decides over their resolution or chronification. However, this CNS-intrinsic cross-talk is … Abstract After acute lesions in the central nervous system (CNS), the interaction of microglia, astrocytes, and infiltrating immune cells decides over their resolution or chronification. However, this CNS-intrinsic cross-talk is poorly characterized. Analyzing cerebrospinal fluid (CSF) samples of Multiple Sclerosis (MS) patients as well as CNS samples of female mice with experimental autoimmune encephalomyelitis (EAE), the animal model of MS, we identify microglia-derived TGFα as key factor driving recovery. Through mechanistic in vitro studies, in vivo treatment paradigms, scRNA sequencing, CRISPR-Cas9 genetic perturbation models and MRI in the EAE model, we show that together with other glial and non-glial cells, microglia secrete TGFα in a highly regulated temporospatial manner in EAE. Here, TGFα contributes to recovery by decreasing infiltrating T cells, pro-inflammatory myeloid cells, oligodendrocyte loss, demyelination, axonal damage and neuron loss even at late disease stages. In a therapeutic approach in EAE, blood-brain barrier penetrating intranasal application of TGFα attenuates pro-inflammatory signaling in astrocytes and CNS infiltrating immune cells while promoting neuronal survival and lesion resolution. Together, microglia-derived TGFα is an important mediator of glial-immune crosstalk, highlighting its therapeutic potential in resolving acute CNS inflammation.

Dissection of Neurotropic Theiler's Murine Encephalomyelitis Virus Induced Brain Atrophy in Single <scp>MHC</scp> Class I Mice of <scp>C57BL</scp>/6 Background

2025-06-19

Katheryn Wininger , Katayoun Ayasoufi , Delaney M Anani-Wolf +4 more | PubMed

ABSTRACT Brain atrophy is a common feature of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and more recently SARS‐CoV‐2 infection for which the neuroinflammatory mechanism is not fully … ABSTRACT Brain atrophy is a common feature of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and more recently SARS‐CoV‐2 infection for which the neuroinflammatory mechanism is not fully understood. Nevertheless, neuroinflammation and CD8 T cell accumulation is frequently observed in postmortem brain tissue of patients with neurodegeneration. We therefore developed a murine model of brain atrophy using the Theiler's murine encephalomyelitis virus (TMEV) infection model of multiple sclerosis. We employ single major histocompatibility complex (MHC) class I molecule conditional knockout mice generated by our program to analyze the contribution of immune cell infiltration and onset of atrophy. TMEV infected C57BL/6 mice that singularly express H‐2K b or H‐2D b were evaluated. TMEV infection of these mice resulted in ventricular atrophy at 14 d.p.i. However, H‐2D b expressing mice presented with significantly greater and continuous ventricular atrophy compared to H‐2K b expressing mice and MHC class I knockout control mice. Flow cytometric analysis revealed H‐2D b expressing mice had greater brain infiltrating CD8 T cell responses at 7 and 28 dpi which correlated with the extent of ventricular atrophy. Meanwhile, H‐2K b and MHC class I knockout mice also had distinct positive correlations with ventricular atrophy and global neuroinflammation in general. These findings support the role of immune cell infiltration into the CNS as a putative mechanism of ventricular atrophy following TMEV infection, with the progressive enlargement of ventricular atrophy observed in H‐2D b mice being associated with the presence of long‐lived memory CD8 T cells residing in the brain.