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Cited by 618Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

Microglial dysfunction in brain aging and Alzheimer's disease

Open access
Mosher, Kira Irving, Wyss-Coray, Tony·2014·Biochemical Pharmacology
DOI 10.1016/j.bcp.2014.01.008PMC PMC3972294
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Abstract

Microglia, the immune cells of the central nervous system, have long been a subject of study in the Alzheimer's disease (AD) field due to their dramatic responses to the pathophysiology of the disease. With several large-scale genetic studies in the past year implicating microglial molecules in AD, the potential significance of these cells has become more prominent than ever before. As a disease that is tightly linked to aging, it is perhaps not entirely surprising that microglia of the AD brain share some phenotypes with aging microglia. Yet the relative impacts of both conditions on microglia are less frequently considered in concert. Furthermore, microglial "activation" and "neuroinflammation" are commonly analyzed in studies of neurodegeneration but are somewhat ill-defined concepts that in fact encompass multiple cellular processes. In this review, we have enumerated six distinct functions of microglia and discuss the specific effects of both aging and AD. By calling attention to the commonalities of these two states, we hope to inspire new approaches for dissecting microglial mechanisms.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that microglial changes in normal brain aging and Alzheimer’s disease overlap substantially, with aging possibly priming cells toward exaggerated, dysfunctional responses. It organizes microglial biology into six functional domains and uses recent genetic and phenotypic evidence to propose a framework for studying shared mechanisms.

Key findings

  • Recent genetic studies link immune and microglial genes to late-onset Alzheimer’s disease, including TREM2, CD33, HLA-DRB4-DRB1, CLU, CR1, and TYROBP; the paper notes that a PubMed search for microglia and Alzheimer’s disease returned 2,397 citations.
  • Aging and Alzheimer’s microglia share features such as increased marker expression, altered morphology, reduced motility, and impaired phagocytosis or proteostasis, but the review stresses that the two states are not equivalent; Alzheimer’s may represent an exaggerated or compounded state.
  • The review proposes six microglial effector domains—proliferation and senescence, morphological transformation, motility and migration, intercellular communication, phagocytosis, and proteostasis—and discusses age- and disease-related changes in each.
  • Evidence on M1/M2 polarization is mixed: both pro- and anti-inflammatory markers can rise with age, and outcomes depend on injury context; microglial amyloid-beta clearance appears more effective early and less effective late in disease.

Methods

  • Narrative review, not primary research; no experimental sample or new data are reported.
  • Synthesizes genetic association studies, human postmortem and imaging work, and rodent or in vitro studies to compare microglial phenotypes in aging and Alzheimer’s disease.
  • Main analytic approach is conceptual: define six functional categories and examine reported alterations within each across aging and Alzheimer’s disease.

Limitations

  • The authors state that most observations are descriptive and show what microglial aging looks like rather than why it occurs; underlying mechanisms remain unclear.
  • They note that microglial “activation” and M1/M2 categories are ill-defined and context-dependent, and that it is unresolved whether microglial activity is causative or reactive in neurodegeneration.
  • Evident from the text: as a review, it lacks a systematic search or quality assessment and quantitative synthesis; much evidence comes from mouse models and in vitro systems, with limited direct human causal data.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.bcp.2014.01.008

Cites

159 of 159 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 94 cited sources checked · 0 supported · 0 flagged

  • Findingreasoning

    Age-related microglial changes can include dysfunctional and hyper-reactive responses, not only loss of function.

    “The hallmarks of microglial aging may also sometimes be characterized as dysfunctional and even hyper-reactive responses.”
    Quote in the paperSubstantial claim
  • Findingnone given

    The effectiveness of microglial functions appears to decline with age.

    “the efficacy of these functions seems to deteriorate with age”
    Quote in the paperSubstantial claim
  • Premisecitation

    A 2009 genome-wide association study identified variants at CLU and CR1 associated with Alzheimer's disease.

    “A 2009 GWAS identified variants at CLU and CR1 associated with AD [33]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Lambert J-C Heath S Even G Campion D Sleegers K Hiltunen M Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease Nature Publishing Group 2009 1 7 19734903

      Not checked in the free run.

  • Premisecitation

    A genome-wide association study identified a novel association for late-onset Alzheimer's disease in the HLA-DRB4-DRB1 region.

    “a genome-wide association study (GWAS) identified a novel association for late onset Alzheimer’s disease (LOAD) in the HLA-DRB4-DRB1 region”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Lambert J-C Ibrahim-Verbaas CA Harold D Naj AC Sims R Bellenguez C Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease Nat Genet 2013 PMC3896259 24162737 source

      Not checked in the free run.

  • Premisecitation

    TREM2 and TYROBP mediate phagocytosis of bacteria and apoptotic cells.

    “Together, TREM2 and TYROBP mediate phagocytosis of bacteria and apoptotic cells [27, 28].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27] Neumann H Daly MJ Variant TREM2 as risk factor for Alzheimer’s disease N Engl J Med 2013 368 2 182 4 23151315 source

      Not checked in the free run.

    • cites [28] Hsieh CL Koike M Spusta SC Niemi EC Yenari M Nakamura MC A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia J Neurochem 2009 109 4 1144 56 19302484 PMC3087597 source

      Not checked in the free run.

  • May combine two claims. 19
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Premisecitation

    Systemic infections and inflammation activate microglia and drive or worsen neurodegeneration.

    “Systemic infections and inflammation also activate microglia and drive and exacerbate neurodegeneration [8, 9]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [8] Cunningham C Campion S Teeling J Felton L Perry VH The sickness behaviour and CNS inflammatory mediator profile induced by systemic challenge of mice with synthetic double-stranded RNA (poly I:C) Brain Behavior and Immunity 2007 21 4 490 502 17321719 source

      Not checked in the free run.

    • cites [9] Krstic D Madhusudan A Doehner J Vogel P Notter T Imhof C Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice J Neuroinflammation 2012 9 1 1 1 22747753 PMC3483167 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Obesity stimulates microglia and increases recruitment of peripheral monocytes to the central nervous system.

    “Recent studies have also found that obesity stimulates microglia and enhances the recruitment of peripheral monocytes to the CNS [16, 17]).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] Puig KL Floden AM Adhikari R Golovko MY Combs CK Amyloid Precursor Protein and Proinflammatory Changes Are Regulated in Brain and Adipose Tissue in a Murine Model of High Fat Diet-Induced Obesity PLoS ONE 2012 7 1 e30378 22276186 PMC3261903 source

      Not checked in the free run.

    • cites [17] Buckman LB Hasty AH Flaherty DK Buckman CT Thompson MM Matlock BK Obesity induced by a high-fat diet is associated with increased immune cell entry into the central nervous system Brain Behavior and Immunity 2013 35 C 33 42 PMC3858467 23831150 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TYROBP is increased in late-onset Alzheimer's disease and TREM2 is upregulated in plaque-associated microglia.

    “TYROBP is increased in LOAD and TREM2 is upregulated in plaque-associated microglia [26, 30]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [26] Zhang B Gaiteri C Bodea L-G Wang Z Mcelwee J Podtelezhnikov Alexei A Integrated Systems Approach Identifies Genetic Nodes and Networks in Late-Onset Alzheimer’s Disease Cell 2013 153 3 707 720 23622250 PMC3677161 source

      Not checked in the free run.

    • cites [30] Frank S Burbach GJ Bonin M Walter M Streit W Bechmann I TREM2 is upregulated in amyloid plaque-associated microglia in aged APP23 transgenic mice Glia 2008 56 13 1438 1447 18551625 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Obesity is linked to Alzheimer's disease and is promoted by aging.

    “Obesity, for example, has been linked to AD and is promoted by aging (reviewed in ref. [14]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Lee EB Obesity, leptin, and Alzheimer’s disease Annals of the New York Academy of Sciences 2011 1243 1 15 29 22211890 PMC3564488 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Systemic inflammaging could drive microglial aging and prime exaggerated responses that contribute to neurodegeneration.

    “systemic inflammaging itself could also drive microglia aging, priming the cells to eventually react with exaggerated responses that actually contribute to neurodegeneration”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Microglia in the healthy brain are dynamic and sample the extracellular space through ramified processes.

    “microglia endlessly sample the extracellular space by extending numerous ramified processes”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] Davalos D Grutzendler J Yang G Kim JV Zuo Y Jung S ATP mediates rapid microglial response to local brain injury in vivo Nat Neurosci 2005 8 6 752 758 15895084 source

      Not checked in the free run.

    • cites [6] Nimmerjahn A Kirchhoff F Helmchen F Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo Science 2005 308 5726 1314 8 15831717 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Clusterin is secreted by astrocytes, complexes with soluble Aβ, is present in plaques, and directly activates microglia.

    “Clusterin, which is secreted by astrocytes, has been found to complex to soluble Aβ [35], is present in plaques [36–38], and directly activates microglia [39].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [35] Ghiso J Matsubara E Koudinov A Choi-Miura NH Tomita M Wisniewski T The cerebrospinal-fluid soluble form of Alzheimer’s amyloid beta is complexed to SP-40,40 (apolipoprotein J), an inhibitor of the complement membrane-attack complex The Biochemical journal 1993 293 Pt 1 27 30 8328966 PMC1134315 source

      Not checked in the free run.

    • cites [36] Choi-Miura NH Ihara Y Fukuchi K Takeda M Nakano Y Tobe T SP-40,40 is a constituent of Alzheimer’s amyloid Acta neuropathologica 1992 83 3 260 4 1373021 source

      Not checked in the free run.

    • cites [37] McGeer PL Kawamata T Walker DG Distribution of clusterin in Alzheimer brain tissue Brain Res 1992 579 2 337 41 1378350 source

      Not checked in the free run.

    • cites [38] Kida E Choi-Miura NH Wisniewski KE Deposition of apolipoproteins E and J in senile plaques is topographically determined in both Alzheimer’s disease and Down’s syndrome brain Brain Res 1995 685 1–2 211 6 7583250 source

      Not checked in the free run.

    • cites [39] Xie Z Harris-White ME Wals PA Frautschy SA Finch CE Morgan TE Apolipoprotein J (clusterin) activates rodent microglia in vivo and in vitro J Neurochem 2005 93 4 1038 1046 15857407 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisereasoning

    Microglia exist in the adult brain as protective agents.

    “microglia exist in the adult brain as a protective agent”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Clusterin may function similarly to APOE in trafficking and clearing Aβ, potentially through interactions with microglia.

    “it has been suggested that clusterin functions similarly to APOE in trafficking and clearing Aβ, potentially through interactions with microglia (reviewed in ref. [40])”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Cole GM Ard MD Influence of lipoproteins on microglial degradation of Alzheimer’s amyloid beta-protein Microsc Res Tech 2000 50 4 316 24 10936886 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Impairments in phagocytic removal of apoptotic cells or bacteria could worsen these effects and ultimately lead to neural degeneration.

    “Impairments in the phagocytic removal of apoptotic cells or bacteria could exacerbate these effects and ultimately lead to neural degeneration.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Obesity could contribute to low-grade chronic inflammation both peripherally and within the brain.

    “Obesity could therefore also contribute to low-grade chronic inflammation peripherally and within the brain.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    CR1 could help clear Aβ by mediating phagocytosis of C3b-opsonized amyloid, while blocking CR1 can reduce proinflammatory factors and neurotoxicity by Aβ-treated microglia.

    “there is evidence that CR1 could help clear Aβ by mediating phagocytosis of C3b-opsonized amyloid [41] [42], blocking CR1 can also reduce the production of proinflammatory factors and neurotoxicity by microglia that have been treated with Aβ [41]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [41] Crehan H Hardy J Pocock J Blockage of CR1 prevents activation of rodent microglia Neurobiology of Disease 2013 54 C 139 149 23454195 source

      Not checked in the free run.

    • cites [42] Rogers J Li R Mastroeni D Grover A Leonard B Ahern G Peripheral clearance of amyloid beta peptide by complement C3-dependent adherence to erythrocytes Neurobiol Aging 2006 27 12 1733 9 16290270 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Age-related immune changes do not appear to better equip microglia to combat aging and Alzheimer's pathology; instead, the cells become more proinflammatory and impaired in protective functions.

    “these changes do not appear to better equip microglia to combat age-related and AD pathology, and if anything the cells become more proinflammatory and impaired in their normal protective functions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Alzheimer's disease mechanisms may worsen age effects on microglial morphology; aged transgenic APP mice have larger cell bodies and shorter processes than younger transgenic mice, with further exacerbation in plaque-containing brain areas.

    “microglia in aged transgenic APP mice were found to have larger cell bodies and shorter processes overall compared to those in younger transgenic mice, with these phenotypes being further exacerbated in brain areas containing plaque pathology [72]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Koenigsknecht-Talboo J Meyer-Luehmann M Parsadanian M Garcia-Alloza M Finn MB Hyman BT Rapid Microglial Response Around Amyloid Pathology after Systemic Anti-A Antibody Administration in PDAPP Mice Journal of Neuroscience 2008 28 52 14156 14164 19109498 PMC2743894 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglial proliferative capacity is not lost with age and may be increased under certain conditions compared with young brains.

    “the microglia proliferative capacity is not lost with age, and in fact may be increased under certain conditions compared to young brains [47]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Hua K Schindler MK Mcquail JA Forbes ME Riddle DR Regionally Distinct Responses of Microglia and Glial Progenitor Cells to Whole Brain Irradiation in Adult and Aging Rats PLoS ONE 2012 7 12 e52728 23300752 PMC3530502 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglia retain the ability to proliferate and self-renew in adulthood, although this is infrequent under normal physiological conditions.

    “Microglia retain the ability to proliferate and self-renew in adulthood, though this occurs in response to various injury signals and is a relatively infrequent event under normal physiological conditions [45, 46].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Lawson LJ Perry VH Gordon S Turnover of resident microglia in the normal adult mouse brain Neuroscience 1992 48 2 405 15 1603325 source

      Not checked in the free run.

    • cites [46] Xu H Chen M Mayer EJ Forrester JV Dick AD Turnover of resident retinal microglia in the normal adult mouse Glia 2007 55 11 1189 1198 17600341 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Average microglial soma size does not differ between ages, but soma size variability is greater in aged animals.

    “while the average microglia soma size was not different between ages, there was greater variability in soma size in aged animals [50]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Tremblay M-È Zettel ML Ison JR Allen PD Majewska AK Effects of aging and sensory loss on glial cells in mouse visual and auditory cortices Glia 2012 60 4 541 558 22223464 PMC3276747 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aging rodent microglia have significantly reduced arborization size and complexity.

    “the arborizations of aging rodent microglia are significantly reduced in size [50, 51, 57] and complexity [51, 71]”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [50] Tremblay M-È Zettel ML Ison JR Allen PD Majewska AK Effects of aging and sensory loss on glial cells in mouse visual and auditory cortices Glia 2012 60 4 541 558 22223464 PMC3276747 source

      Not checked in the free run.

    • cites [51] Damani MR Zhao L Fontainhas AM Amaral J Fariss RN Wong WT Age-related alterations in the dynamic behavior of microglia Aging Cell 2011 10 2 263 76 21108733 PMC3056927 source

      Not checked in the free run.

    • cites [57] Hefendehl JK Neher JJ Sühs RB Kohsaka S Skodras A Jucker M Homeostatic and injury-induced microglia behavior in the aging brain Aging Cell 2013 n/a n/a PMC4326865 23953759

      Not checked in the free run.

    • cites [71] Sierra A Gottfried-Blackmore AC Mcewen BS Bulloch K Microglia derived from aging mice exhibit an altered inflammatory profile Glia 2007 55 4 412 24 17203473 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Microglia are likely a very long-lived cell population.

    “have led to the suggestion that microglia are a very long-lived cell population”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Systemic inflammaging may mirror microglial aging phenotypes and could also play a causal role.

    “this systemic inflammaging may not only mirror microglial aging phenotypes but could have a causal role as well.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premiseown data

    Most data on microglial aging describe what it looks like rather than why it occurs.

    “The observations described here are mainly descriptive in nature; strictly speaking, most of the data on the subject indicate what microglial aging looks like but not why it happens.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given

    Microglial functions are inherently linked, and one response profile likely affects the outcome of another.

    “it is certainly important to remember that all of these functions are inherently linked, and that the profile of one response is likely to influence the outcome of another.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Phagocytosis has received little attention in aging research.

    “while phagocytosis has generally received little attention in the field of aging”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    A general proinflammatory phenotype accompanies aging in mammals at the system-wide level.

    “a general proinflammatory phenotype accompanies aging in mammals at system-wide level”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Evidence is insufficient to conclude that microglia perform true phagocytosis of amyloid-beta.

    “But in point of fact, is has been argued that there has yet to be sufficient evidence that microglia are capable of true phagocytosis of Aβ [149]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [149] Prokop S Miller KR Heppner FL Microglia actions in Alzheimer’s disease Acta neuropathologica 2013 24224195 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Protein aggregation is a major result of declining proteostasis and is especially prominent in age-related neurodegenerative diseases including Huntington's, Parkinson's, and Alzheimer's disease.

    “A major consequence of declining proteostasis is the aggregation of proteins, which is particularly prominent in age-associated neurodegenerative diseases such as Huntington’s, Parkinson’s, and Alzheimer’s disease [144].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [144] Taylor RC Dillin A Aging as an Event of Proteostasis Collapse Cold Spring Harbor Perspectives in Biology 2011 3 5 a004440 a004440 21441594 PMC3101847 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Proteostasis mechanisms other than phagocytic engulfment are rarely studied in microglia research.

    “proteostasis mechanisms beyond phagocytic engulfment are rarely studied in the field of microglia.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Aged microglia may be primed so that additional stimuli make them over-reactive, eventually causing neurodegeneration and sometimes progression to Alzheimer's disease.

    “Aged microglia may thus be primed such that additional stimuli cause them to become over-reactive, eventually leading to neurodegeneration and, in some cases, progression to AD.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    It is unclear whether microglial activation causes neurodegeneration or is a reaction to it.

    “whether microglia activation is a causative factor (hence, “bad for”) or reactive to (perhaps, “good for”) neurodegeneration is unclear.”
    Quote in the paperSubstantial claim
29 of 29

  • The paper relies on this without support.

    Aging and Alzheimer's disease microglial phenotypes are not equivalent.

    “Thus while aging and AD microglial phenotypes are by no means equivalent”

  • The paper relies on this without support.

    The intersection of aging and Alzheimer's disease microglial biology has not been thoroughly explored.

    “the intersection of these two components has not been thoroughly explored”

  • The paper relies on this without support.

    The consequences of age-related microglial changes in normal aging are not well understood.

    “our understanding of the consequences of these changes within simply normal aging is also limited”

  • The paper relies on this without support.

    Microglial activation and neuroinflammation are ill-defined concepts that encompass multiple cellular processes.

    “microglial “activation” and “neuroinflammation” are commonly analyzed in studies of neurodegeneration but are somewhat ill-defined concepts”

  • The paper relies on this without support.

    Protein homeostasis mechanisms are essential for cellular and organismal health because they maintain protein quality control and prevent accumulation of misfolded proteins.

    “Protein homeostasis (proteostasis) mechanisms are crucial for cellular and organismal health as they ensure protein quality control and prevent the accumulation of aberrantly formed proteins.”

  • The paper relies on this without support.

    Loss of proteostasis is a common feature of general aging and involves many pathways, including impaired chaperone-mediated folding, trafficking, degradation, and autophagy.

    “Loss of proteostasis is a common theme in studies of general aging that encompasses many pathways, including impairments in chaperone-mediate protein folding and stability, protein trafficking, protein degradation, and autophagy.”

  • The paper relies on this without support.

    Systemic immune challenges activate microglia.

    “Since systemic immune challenges trigger microglial activation”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In the aging brain, microglia lose their homeostatic molecular signature and show functional impairments such as increased pro-inflammatory cytokines, elevated ROS, and lysosomal deposits.

    “In the aging brain and in neurodegeneration, microglia lose their homeostatic molecular signature and show profound functional impairments, such as increased production of pro-inflammatory cytokines, elevated generation of reactive oxygen species (ROS) and build-up of dysfunctional lysosomal deposits indicative of impaired phagocytosis2.”

    From Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain (2020) · cites this paper as [2]

    Section 4.4 reports generally increased pro-inflammatory cytokine release from aged microglia, altered marker expression, and increased oxidative stress with aging. Section 4.5 reports lysosomal inclusions in aged microglia, but says impaired degradation is a possible interpretation and that age-related effects on phagocytosis remain poorly defined. The source therefore supports the broad pattern, but not a definitive loss of a homeostatic molecular signature or the claim that the deposits establish impaired phagocytosis. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Aged microglia are one of the main sources of increased ROS levels in the aging brain.

    “Aged microglia are one of the main sources of increased ROS levels in the aging brain2, and excessive microglial ROS production might contribute to age-related CNS dysfunctions.”

    From Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain (2020) · cites this paper as [2]

    Section 4.4 says oxidative stress increases with aging and that NOX2 contributes to microglial ROS production in an LPS-induced inflammation model. It calls microglial NADPH oxidase a believed primary ROS source in the context of Alzheimer’s disease, but does not establish aged microglia as a main source of increased ROS in the aging brain generally. No page number was provided in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Aged microglia show increased production of inflammatory cytokines such as TNF-α, IL-1β and IL-6 under baseline conditions and excessive cytokine release upon immune challenge.

    “Another characteristic of aged microglia is the increased production of inflammatory cytokines such as TNF-α, IL-1β and IL-6 under baseline conditions and excessive cytokine release upon immune challenge2.”

    From Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain (2020) · cites this paper as [2]

    Section 4.4 (page unavailable) says proinflammatory cytokine production and release by aged microglia are generally increased, and identifies TNF-α, IL-1β and IL-6 as markers often elevated in aged mice. But it says secretion depends on the stimulant and notes studies finding no age-related activation differences without pathological insults; it does not establish increased production of all three under baseline conditions or consistently excessive release upon immune challenge. The Conclusion (page unavailable) presents over-reactivity to additional stimuli as a possibility. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Lysosomes become dysfunctional in aged microglia.

    “Lastly, there is emerging evidence that lysosomes become dysfunctional in aged microglia2.”

    From Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain (2020) · cites this paper as [2]

    Section 4.5 (Phagocytosis; page unavailable) reports lysosomal inclusions in aged rodent microglia and says these may indicate impaired degradation of ingested material. That is emerging evidence consistent with the claim, but the paper does not establish that the lysosomes themselves become dysfunctional. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Perturbations in microglial activity, often associated with aging, can affect the effective clearance of neuron-derived Aβ fibrils, leading to increased plaque formation and progression of cognitive and behavioral impairments.

    “However, perturbations in microglial activity, often associated with aging, can affect the effective clearance of these neuron-derived Aβ fibrils, leading to increased plaque formation and the progression of cognitive and behavioral impairments (17–20).”

    From Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model (2025) · cites this paper as [18]

    Section 4.5 (Phagocytosis; page unavailable) reports that aged microglia take up less Aβ and that microglial clearance becomes less efficient in later disease stages. But section 4.6 (Proteostasis; page unavailable) treats protection through Aβ clearance as an assumption and cites a mouse study in which microglial ablation did not change plaque deposition. The paper does not establish the claimed chain from impaired clearance of neuron-derived Aβ fibrils to increased plaques and progressive cognitive and behavioral impairments. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Landreth, 2009, Curr Top Microbiol Immunol, 336, 137

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Authors
Mosher, K. I., & Wyss-Coray, T.
Affiliations
Stanford Medicine (US)
ORCID
Mosher, Kira Irving
Venue
Biochemical Pharmacology
Publisher
Elsevier BV
Published
2014-04
Volume
88
Issue
4
Pages
594-604
ISSN
0006-2952 (ISSN-L)
DOI
10.1016/j.bcp.2014.01.008
PMC
PMC3972294
OpenAlex
W2082414904
Cited by
618
References
159
Citations by year
2026: 25 · 2025: 53 · 2024: 46 · 2023: 49 · 2022: 53 · 2021: 69 · 2020: 50 · 2019: 48 · 2018: 51 · 2017: 52 · 2016: 43 · 2015: 52 · 2014: 27
FWCI
4.69
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Biochemical Pharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute on Aging (F31AG040877, AG03144, AG045034, R01AG030144, R01AG045034)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
microglia, Alzheimer's disease, brain aging, microglial dysfunction, neuroinflammation, microglial activation, neurodegeneration, microglial phenotype, genetic risk factors
MeSH terms
Aging, Alzheimer Disease, Brain, Humans, Microglia

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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