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Microglia in Alzheimer’s disease
Open accessAbstract
Proliferation and activation of microglia in the brain, concentrated around amyloid plaques, is a prominent feature of Alzheimer’s disease (AD). Human genetics data point to a key role for microglia in the pathogenesis of AD. The majority of risk genes for AD are highly expressed (and many are selectively expressed) by microglia in the brain. There is mounting evidence that microglia protect against the incidence of AD, as impaired microglial activities and altered microglial responses to β-amyloid are associated with increased AD risk. On the other hand, there is also abundant evidence that activated microglia can be harmful to neurons. Microglia can mediate synapse loss by engulfment of synapses, likely via a complement-dependent mechanism; they can also exacerbate tau pathology and secrete inflammatory factors that can injure neurons directly or via activation of neurotoxic astrocytes. Gene expression profiles indicate multiple states of microglial activation in neurodegenerative disease settings, which might explain the disparate roles of microglia in the development and progression of AD pathology.
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TL;DR
This review synthesizes human genetic and cell-biological evidence that microglia play a dual role in Alzheimer's disease: protective early (TREM2-dependent clearance and compaction of Aβ) and harmful later (complement-mediated synapse engulfment, inflammatory cytokine release, and tau pathology spread). The authors propose that the detrimental microglial state emerges later in disease, complicating therapeutic strategies that target microglia.
Key findings
- Human genetics implicate microglia in late-onset AD: over 20 loci associate with AD risk, and most identified risk genes are expressed selectively or preferentially in microglia; apart from APOE, common variants confer only minor effects (∼10–20%) on AD risk.
- The TREM2 R47H variant (carried by <0.5% of most populations) increases AD risk approximately threefold and appears to be a loss-of-function mutation impairing TREM2-mediated microglial activation, ligand binding (apoE, apoJ/CLU), and Aβ uptake; Trem2 knockout exacerbates plaque accumulation at later ages (8+ months) in β-amyloidosis mouse models.
- APOE genotype strongly modulates risk: relative to apoE3, a single apoE4 allele confers approximately threefold increased risk and apoE2 approximately twofold reduced risk; apoE4 appears to reduce Aβ clearance and increase plaque deposition.
- Microglia can be harmful: complement (C1q, C3) and microglia mediate synapse loss in amyloid models, CSF1R-inhibitor microglia depletion protects against synapse loss and rescues behavioral deficits, and microglia are implicated in tau spread; in microglia-depleted brains plaque size increased ∼13% over 1 wk.
- Transcriptional profiling identifies a disease-associated microglial (DAM) state with reduced homeostatic genes (e.g., Cx3cr1, P2ry12, Tmem119) and induced neurodegeneration genes (e.g., Apoe, Axl, Csf1, Clec7a, Cst7, Igf1, Itgax), with subtle two- to threefold increases in Trem2 and Tyrobp mRNAs; DAM induction depends largely on TREM2.
Methods
- Narrative review (Hansen, Hanson, and Sheng) synthesizing human genetics (GWAS and rare-variant studies), mouse model studies, and microglial transcriptomic profiling; no primary data are generated.
- Evidence reviewed includes GWAS-identified AD risk loci (Table 1), TREM2 and other microglial risk genes, complement-pathway and microglia-depletion experiments in amyloid and tau mouse models (Fig. 3), and RNA-sequencing/single-cell studies of microglial activation states.
- The authors integrate these findings into a proposed two-phase model of microglial function in AD pathogenesis.
Limitations
- Stated by the paper: exactly how microglia are involved in the disease mechanism "is not settled"; evidence for microglial-mediated neuronal damage comes "mostly in mouse models"; TREM2 studies in tau models report seemingly conflicting roles (neuroprotective in PS19 vs. neurotoxic in hTau) that the authors attribute partly to analysis at different disease stages; whether the TREM2-dependent transcriptional response is helpful, damaging, or incidental in different disease contexts requires further study.
- Stated by the paper: studies of microglial gene expression in purified microglia or at the single-cell level from AD brains "have lagged behind" mouse work, and there was "surprisingly limited overlap" in aging-regulated microglial genes between human and mouse, underscoring the need for human microglia profiling at different disease stages and genotypes.
- Evident from the text: many mechanistic conclusions rest on mouse models that overexpress mutant APP/PS1 or tau transgenes, and the authors note conflicting complement-pathway results (e.g., C3 knockout/inhibition reported both to provide neuroprotection and to increase amyloid burden), so causal direction in humans remains uncertain.
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Claims the paper makes
86 Not checked yet · 27 Own interpretation · 6 No basis given · 4 Sources not found
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In the paper
“a striking feature of the identified risk genes is that the majority of them are expressed selectively or preferentially in microglia relative to other cell types in the brain (Fig. 1 A; Srinivasan et al., 2016; Zhang et al., 2016).”
§ Microglia in Alzheimer’s disease > Human genetic evidence for microglia involvement in late-onset AD
What the sources say
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In the paper
“In a meta-analysis of microglial transcriptomic profiles from various models of CNS diseases (neurodegenerative, demyelinating, ischemic, infectious, inflammatory, and neoplastic), we identified several modules of coordinately regulated genes, including a neurodegeneration-associated module highly similar to the DAM genes mentioned previously (Friedman et al., 2017).”
§ Microglia in Alzheimer’s disease > Microglial activation states defined by transcriptional profiling
What the sources say
- Not checked yetcites Friedman et al., 2017
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In the paper
“rare genetic variants associated with AD (found by gene sequencing or exome array) have also implicated microglia in determining the risk of AD (Guerreiro et al., 2013; Jonsson et al., 2013; Sims et al., 2017).”
§ Microglia in Alzheimer’s disease > Human genetic evidence for microglia involvement in late-onset AD
What the sources say
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In the paper
“This broad trend implicates microglial dysfunction as a contributing factor, rather than an attendant feature, of AD pathogenesis.”
§ Microglia in Alzheimer’s disease > Human genetic evidence for microglia involvement in late-onset AD
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In the paper
“Aβ aggregates are much more efficiently taken up by microglia when Aβ is complexed with lipoproteins such as LDL, apoE, and CLU/apoJ (Terwel et al., 2011; Yeh et al., 2016).”
§ Microglia in Alzheimer’s disease > Protective role of TREM2 and microglia in AD > Phagocytosis and clearance of Aβ and cellular debris
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The TREM2 mutation most clearly associated with AD (R47H, carried by <0.5% of most populations) increases the risk of AD approximately threefold (Guerreiro et al., 2013; Jonsson et al., 2013).”
§ Microglia in Alzheimer’s disease > Human genetic evidence for microglia involvement in late-onset AD
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In recent years, however, biological advances stemming from human genetics data have removed any doubt that microglia play an important role in the pathogenesis of AD.”
§ Microglia in Alzheimer’s disease > Introduction
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In the paper
“During normal brain development, mounting evidence indicates that microglia engulf synapses and sculpt synaptic connections via a novel role for complement, a component of the innate immune system that enhances the clearance of microbes or damaged cells by phagocytes (Boulanger, 2009; Stephan et al., 2012; Chung et al., 2015).”
§ Microglia in Alzheimer’s disease > Detrimental activities of microglia in AD > Microglia, complement, and synapse engulfment
What the sources say
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Microglial engulfment of synapses likely varies with different developmental stages, brain regions, and disease states.”
§ Microglia in Alzheimer’s disease > Detrimental activities of microglia in AD > Microglia, complement, and synapse engulfment
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“SHIP1 dephosphorylates phosphatidylinositol (3,4,5)-trisphosphate to phosphatidylinositol (3,4)-bisphosphate at the plasma membrane, altering the outcomes of PI3K activation.”
§ Microglia in Alzheimer’s disease > Potential involvement of other AD risk genes in microglial function
plaindirect- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 47
In the paper
“Using these modules to probe the single-cell expression data of Keren-Shaul et al. (2017), we revealed a unique subset of microglia, distinct from the DAM cells, that expressed an interferon-related gene module and increased numerically in brains with β-amyloid pathology (Friedman et al., 2017).”
§ Microglia in Alzheimer’s disease > Microglial activation states defined by transcriptional profiling
What the sources say
- Not checked yetcites Friedman et al., 2017
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“We also review the evidence that, once activated, microglia can have harmful actions in AD, such as being the source of inflammatory factors and mediating the engulfment of neuronal synapses.”
§ Microglia in Alzheimer’s disease > Introduction
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In this review, we consider the genetic and cell biological data indicating that microglia have protective functions that restrain the toxic accumulation of β-amyloid and prevent the development of AD.”
§ Microglia in Alzheimer’s disease > Introduction
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“TREM2–ligand interactions are impaired by TREM2 variants that increase AD risk (Wang et al., 2015; Kober et al., 2016; Yeh et al., 2016; Song et al., 2017), implying that these AD variants are at least partial loss-of-function mutants.”
§ Microglia in Alzheimer’s disease > Protective role of TREM2 and microglia in AD
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“TREM2 functions as a cell surface receptor on microglia; via its interaction with the activating adaptor protein DAP12 (encoded by the TYROBP gene), TREM2 stimulation initiates signal transduction pathways that promote microglial chemotaxis, phagocytosis, survival, and proliferation (Takahashi et al., 2005; Hsieh et al., 2009; Kleinberger et al., 2014; Poliani et al., 2015; Wang et al., 2015, 2016”
§ Microglia in Alzheimer’s disease > Protective role of TREM2 and microglia in AD
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“TREM2 is required for microglial phagocytosis of a variety of substrates, including apoptotic neurons, bacteria, LDL and other lipoproteins, and Aβ (Takahashi et al., 2005; N’Diaye et al., 2009; Kleinberger et al., 2014; Atagi et al., 2015; Yeh et al., 2016).”
§ Microglia in Alzheimer’s disease > Protective role of TREM2 and microglia in AD > Phagocytosis and clearance of Aβ and cellular debris
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The interaction of TREM2 with its lipoprotein ligands (LDL, APOE, and CLU) was impaired by the AD-linked mutations of TREM2 (R47H, R62H, and D87N) and completely abolished by Nasu–Hakola disease–linked mutations (Y38C and T66M; Atagi et al., 2015; Bailey et al., 2015; Yeh et al., 2016).”
§ Microglia in Alzheimer’s disease > Protective role of TREM2 and microglia in AD > Phagocytosis and clearance of Aβ and cellular debris
What the sources say
- Not checked yetcites Atagi et al., 2015
- Not checked yetcites Bailey et al., 2015
- Not checked yetcites Yeh et al., 2016 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Because R47H appears to be a loss-of-function mutation that impairs TREM2-mediated microglial activation (see the following sections), the study of TREM2 has been instrumental in establishing the view that microglia normally operate in a protective capacity against AD (Jay et al., 2017b; Ulrich et al., 2017; Yeh et al., 2017).”
§ Microglia in Alzheimer’s disease > Human genetic evidence for microglia involvement in late-onset AD
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“TREM2-deficient microglia showed reduced uptake of Aβ-lipoprotein complexes in vitro (Yeh et al., 2016) and less evidence of Aβ internalization in vivo (Wang et al., 2016; Yuan et al., 2016).”
§ Microglia in Alzheimer’s disease > Protective role of TREM2 and microglia in AD > Phagocytosis and clearance of Aβ and cellular debris
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Notably, TREM2 binds to apolipoproteins apoE and clusterin (CLU; also known as apoJ), which are themselves encoded by AD risk genes (Atagi et al., 2015; Bailey et al., 2015; Yeh et al., 2016).”
§ Microglia in Alzheimer’s disease > Protective role of TREM2 and microglia in AD
What the sources say
- Not checked yetcites Atagi et al., 2015
- Not checked yetcites Bailey et al., 2015
- Not checked yetcites Yeh et al., 2016 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“SHIP1 can interact with the phosphorylated ITAM of DAP12, so it may also moderate TREM2 signaling by competing with SYK and PI3K for ITAM occupancy (Peng et al., 2010).”
§ Microglia in Alzheimer’s disease > Potential involvement of other AD risk genes in microglial function
What the sources say
- Not checked yetcites Peng et al., 2010
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“We suggest that the TREM2–apoE axis plays a key role in the microglial clearance of a variety of extracellular and cellular detritus and thus may be generally important for minimizing bystander damage to neurons in neurodegenerative settings.”
§ Microglia in Alzheimer’s disease > Protective role of TREM2 and microglia in AD > Phagocytosis and clearance of Aβ and cellular debris
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“The CD33 genotype–phenotype relationship nicely aligns with that of TREM2: the TREM2 R47H mutation (which increases AD risk) reduces TREM2–ligand binding and ITAM signaling and impairs phagocytosis, whereas the CD33 variant (which reduces AD risk) prevents the CD33–ligand interaction and presumably ITIM signaling and promotes phagocytosis (Bradshaw et al., 2013; Griciuc et al., 2013).”
§ Microglia in Alzheimer’s disease > Potential involvement of other AD risk genes in microglial function
What the sources say
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“the compaction of protofibrillary Aβ into a dense core plaque, which requires apoE and is promoted by TREM2 (Bales et al., 1997b, 1999; Bien-Ly et al., 2012; Wang et al., 2016; Yuan et al., 2016), could be a protective mechanism that limits neurotoxicity of amyloid deposits once they start to build up in the aging brain.”
§ Microglia in Alzheimer’s disease > Protective role of TREM2 and microglia in AD > Congregation around amyloid plaques and barrier formation
What the sources say
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“we discuss how microglia can directly mediate synapse loss (Wu et al., 2015; Spangenberg and Green, 2017) and exacerbate tau pathology (Leyns and Holtzman, 2017).”
§ Microglia in Alzheimer’s disease > Detrimental activities of microglia in AD
What the sources say
- Not checked yetcites Wu et al., 2015
- Not checked yetcites Spangenberg and Green, 2017
- Not checked yetcites Leyns and Holtzman, 2017
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Carriers of the IL1RAP polymorphism also showed reduced signal for microglial activation using a TSPO (translocator protein)-binding positron emission tomography tracer, as well as an increased rate of temporal lobe atrophy and higher likelihood of progression from mild cognitive impairment to AD.”
§ Microglia in Alzheimer’s disease > Potential involvement of other AD risk genes in microglial function
What the sources say
- Not checked yetcites Ramanan et al., 2015
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Collectively, the TREM2 studies suggest several mechanisms by which microglia can protect from accumulation of toxic Aβ species and development of AD: uptake and clearance of soluble Aβ species, phagocytosis of insoluble fibrillar Aβ deposits, induction of the activated state and chemotaxis, and compaction and corralling of amyloid plaques (Fig. 2).”
§ Microglia in Alzheimer’s disease > Protective role of TREM2 and microglia in AD > Congregation around amyloid plaques and barrier formation
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“TREM2-deficient microglia fail to congregate or proliferate around plaques, lack the typical morphological changes of microglial activation, and show increased apoptosis (Jay et al., 2015; Wang et al., 2015, 2016; Mazaheri et al., 2017).”
§ Microglia in Alzheimer’s disease > Protective role of TREM2 and microglia in AD > Congregation around amyloid plaques and barrier formation
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“electron microscopy studies have detected engulfed synaptic material in the developing hippocampus (Paolicelli et al., 2011), but not in the hippocampus of adult mice undergoing synapse loss caused by prion disease (Sisková et al., 2009; Caleo et al., 2012).”
§ Microglia in Alzheimer’s disease > Detrimental activities of microglia in AD > Microglia, complement, and synapse engulfment
What the sources say
- Not checked yetcites Paolicelli et al., 2011 source
- Not checked yetcites Sisková et al., 2009
- Not checked yetcites Caleo et al., 2012
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Synaptic material is observed within microglia by light microscopy, and this synapse engulfment is reduced in C3 or CR3 knockout mice (Schafer et al., 2012).”
§ Microglia in Alzheimer’s disease > Detrimental activities of microglia in AD > Microglia, complement, and synapse engulfment
What the sources say
- Not checked yetcites Schafer et al., 2012 source
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“INPP5D, which encodes the lipid phosphatase SHIP1, is another AD risk gene preferentially expressed in microglia.”
§ Microglia in Alzheimer’s disease > Potential involvement of other AD risk genes in microglial function
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“These protective “corralling” functions were more readily observed for small, early stage plaques and appeared compromised in mice lacking one or both copies of Trem2, as well as in human AD tissues from TREM2 R47H carriers (Condello et al., 2015; Wang et al., 2016; Yuan et al., 2016).”
§ Microglia in Alzheimer’s disease > Protective role of TREM2 and microglia in AD > Congregation around amyloid plaques and barrier formation
What the sources say
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Human microglia in aged brains or in the vicinity of tau pathology may exhibit dystrophic, fragmented morphology, further suggesting that AD develops in the context of reduced neuroprotective microglial function (Streit et al., 2004, 2009).”
§ Microglia in Alzheimer’s disease > Potential involvement of other AD risk genes in microglial function
What the sources say
- Not matchedcites Streit et al., 2004, 2009
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“SHIP1 is involved in a clathrin-independent mode of receptor endocytosis (Boucrot et al., 2015) and inhibits phagocytosis in macrophages (Cox et al., 2001; Kamen et al., 2007).”
§ Microglia in Alzheimer’s disease > Potential involvement of other AD risk genes in microglial function
What the sources say
- Not checked yetcites Boucrot et al., 2015 source
- Not checked yetcites Cox et al., 2001
- Not checked yetcites Kamen et al., 2007
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Studies of C1q, C4, C3, and CR3 knockout mice suggest that the mechanism of developmental synapse pruning in the retinogeniculate system involves C1q tagging of synapses, opsonization of synapses by C3b, and subsequent phagocytosis of synapses by microglia (Stevens et al., 2007; Schafer et al., 2012; Sekar et al., 2016; Fig. 3 A).”
§ Microglia in Alzheimer’s disease > Detrimental activities of microglia in AD > Microglia, complement, and synapse engulfment
What the sources say
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Recent evidence suggests that microglia form a protective barrier around amyloid deposits, compacting amyloid fibrils into a tightly packed and potentially less toxic form, preventing the accretion of new Aβ onto existing plaques, and reducing axonal dystrophy in the nearby neuropil (Condello et al., 2015).”
§ Microglia in Alzheimer’s disease > Protective role of TREM2 and microglia in AD > Congregation around amyloid plaques and barrier formation
What the sources say
- Not checked yetcites Condello et al., 2015 source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although human genetic data argue that proper microglial function protects against AD, there is plentiful evidence that unbridled microglia activity can be harmful to neurons in neurodegenerative disease.”
§ Microglia in Alzheimer’s disease > Detrimental activities of microglia in AD
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“With β-amyloid deposition, however, some microglial processes become static, showing stable association with plaques over days or weeks, with TREM2, DAP12, and phosphotyrosine concentrated in those processes adjacent to plaques (Condello et al., 2015; Yuan et al., 2016).”
§ Microglia in Alzheimer’s disease > Protective role of TREM2 and microglia in AD > Congregation around amyloid plaques and barrier formation
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The microglial gene expression profile induced by amyloid pathology (see later section on transcription) was broadly dampened in TREM2-deficient mice, indicating a key role of TREM2 in the microglial reaction to Aβ pathology (Wang et al., 2015; Keren-Shaul et al., 2017).”
§ Microglia in Alzheimer’s disease > Protective role of TREM2 and microglia in AD > Congregation around amyloid plaques and barrier formation
What the sources say
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Amyloid plaques appear a decade or two before clinical symptoms of AD, but it is tau pathology and synapse loss that correlate best with cognitive impairment during disease progression (Jack et al., 2010).”
§ Microglia in Alzheimer’s disease > Detrimental activities of microglia in AD
What the sources say
- Not checked yetcites Jack et al., 2010 source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“If this relationship between genotype and expression level holds true in microglia, then it might explain the elevated AD risk, because higher SHIP1 level would dampen microglial activation and phagocytosis.”
§ Microglia in Alzheimer’s disease > Potential involvement of other AD risk genes in microglial function
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- The authors state this as an assumption: The relationship between INPP5D SNP rs35349669 genotype and INPP5D expression level observed in whole blood holds true in microglia.
None of the sources cited for this claim have been checked yet.
In the paper
“Genetic knockout of C1q or neutralizing antibodies against C1q protect against synapse loss observed in amyloid-bearing mice or induced by injected Aβ (Fonseca et al., 2004; Hong et al., 2016).”
§ Microglia in Alzheimer’s disease > Detrimental activities of microglia in AD > Microglia, complement, and synapse engulfment
What the sources say
- Not checked yetcites Fonseca et al., 2004
- Not checked yetcites Hong et al., 2016 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The PS19 study looked at 9 mo, when neurodegeneration is extensive, and observed preservation of piriform and entorhinal cortex volume in mice lacking TREM2, whereas tau phosphorylation and aggregation were unchanged (Leyns et al., 2017).”
§ Microglia in Alzheimer’s disease > Detrimental activities of microglia in AD > Microglia and tau pathology
What the sources say
- Not checked yetcites Leyns et al., 2017
plain- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Treatment with CSF1R inhibitors to deplete microglia or disable their proliferation protects against synapse loss and rescues behavioral deficits in amyloidosis mouse models (Olmos-Alonso et al., 2016; Spangenberg et al., 2016).”
§ Microglia in Alzheimer’s disease > Detrimental activities of microglia in AD > Microglia, complement, and synapse engulfment
What the sources say
- Not checked yetcites Olmos-Alonso et al., 2016 source
- Not checked yetcites Spangenberg et al., 2016
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Recent studies of TREM2 function in mouse models of tau pathology reported seemingly conflicting roles, with Trem2 deletion appearing neuroprotective in the PS19 model (Leyns et al., 2017) but neurotoxic in the hTau model (Bemiller et al., 2017)”
§ Microglia in Alzheimer’s disease > Detrimental activities of microglia in AD > Microglia and tau pathology
What the sources say
- Not checked yetcites Leyns et al., 2017
- Not checked yetcites Bemiller et al., 2017
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This suggested that besides the well-known effects of apoE4 on amyloid accumulation, apoE4 may contribute to AD pathogenesis by exacerbating neuroinflammation and tau pathology.”
§ Microglia in Alzheimer’s disease > Detrimental activities of microglia in AD > Microglia and tau pathology
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“this was reportedly accompanied by increased proinflammatory cytokines, tau pathology, and functional deficits (Cho et al., 2011; Lee et al., 2014).”
§ Microglia in Alzheimer’s disease > Detrimental activities of microglia in AD > Microglia and tau pathology
What the sources say
- Not checked yetcites Cho et al., 2011
- Not checked yetcites Lee et al., 2014 source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“Mouse models of β-amyloidosis exhibit elevated C1q levels, with increased synaptic localization of C1q even before plaques have formed (Hong et al., 2016).”
§ Microglia in Alzheimer’s disease > Detrimental activities of microglia in AD > Microglia, complement, and synapse engulfment
What the sources say
- Not checked yetcites Hong et al., 2016 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, although there are conflicting results, most published studies in amyloidosis mouse models suggest that depleting microglia and blocking complement pathway activation may have beneficial effects in AD, at least in terms of synapse and neuron loss (Fig. 3 B).”
§ Microglia in Alzheimer’s disease > Detrimental activities of microglia in AD > Microglia, complement, and synapse engulfment
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“C1q is expressed in the adult brain, and protein levels rise steeply with aging, especially in the hippocampus (Stephan et al., 2013).”
§ Microglia in Alzheimer’s disease > Detrimental activities of microglia in AD > Microglia, complement, and synapse engulfment
What the sources say
- Not checked yetcites Stephan et al., 2013 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“AD-associated genes include CR1 (complement receptor 1), which plays roles in phagocytosis, clearing of immune complexes, and inhibition of complement (Khera and Das, 2009; Fonseca et al., 2016), and CLU/apoJ, which reportedly can function as an inhibitor of the terminal complement complex (Murphy et al., 1989; Tschopp et al., 1993; McDonald and Nelsestuen, 1997).”
§ Microglia in Alzheimer’s disease > Detrimental activities of microglia in AD > Microglia, complement, and synapse engulfment
What the sources say
- Not checked yetcites Khera and Das, 2009
- Not checked yetcites Fonseca et al., 2016 source
- Not checked yetcites Murphy et al., 1989
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Overall, the findings imply that synapse loss around plaques is dynamically regulated by microglia and can be potentially rescued by microglia depletion despite no change or possible increase in amyloid plaque size.”
§ Microglia in Alzheimer’s disease > Detrimental activities of microglia in AD > Microglia, complement, and synapse engulfment
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“β-Amyloid aggregates/fibrils can act as disease-associated molecular patterns and stimulate Toll-like receptors (TLRs) and the NRLP3 inflammasome (Heneka et al., 2013, 2015), resulting in microglial production of TNFα, IL-1β, and other inflammatory cytokines.”
§ Microglia in Alzheimer’s disease > Detrimental activities of microglia in AD > Microglia and neurotoxic inflammatory signaling
What the sources say
- Not matchedcites Heneka et al., 2013, 2015
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“The study in the hTau model looked at 6 mo (long before neuronal loss) and observed greater tau phosphorylation and aggregation in TREM2-deficient mice, arguing for an early protective role of TREM2 in restraining propagation of tauopathy (Bemiller et al., 2017).”
§ Microglia in Alzheimer’s disease > Detrimental activities of microglia in AD > Microglia and tau pathology
What the sources say
- Not checked yetcites Bemiller et al., 2017
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“These studies point to a disease-associated microglial (DAM) state in which expression of a “homeostatic” gene set is reduced (e.g., Cx3cr1, P2ry12, and Tmem119) and another set of “neurodegeneration” genes is highly induced (e.g., Apoe, Axl, Csf1, Clec7a, Cst7, Igf1, Itgax/CD11c, Lilrb4, Lpl, and some major histocompatibility complex class II genes).”
§ Microglia in Alzheimer’s disease > Microglial activation states defined by transcriptional profiling
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“RNA-sequencing studies of human microglia isolated from non-AD brain tissue (Galatro et al., 2017; Gosselin et al., 2017) showed broad similarity with mouse microglial gene expression profiles, although there were many differences such as higher expression of the C2 and C3 complement genes in human microglia.”
§ Microglia in Alzheimer’s disease > Microglial activation states defined by transcriptional profiling
What the sources say
- Not checked yetcites Galatro et al., 2017
- Not checked yetcites Gosselin et al., 2017 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Notably, DAM cells increase in number with progression of amyloidosis, lie spatially close to amyloid plaque, and show evidence of Aβ uptake.”
§ Microglia in Alzheimer’s disease > Microglial activation states defined by transcriptional profiling
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
Soluble oligomeric Aβ is the form that exerts the most toxic effects on neurons.
“A halo of soluble, oligomeric Aβ (the form currently thought to exert the most toxic effects on neurons) likely exists around amyloid plaques.”
The authors state this as an assumption.
The relationship between INPP5D SNP rs35349669 genotype and INPP5D expression level observed in whole blood holds true in microglia.
“If this relationship between genotype and expression level holds true in microglia, then it might explain the elevated AD risk, because higher SHIP1 level would dampen microglial activation and phagocytosis.”
The paper relies on this without support.
Microglia express the C3a and C5a receptors that trigger inflammation in response to complement activation.
“and they express the C3a and C5a receptors that trigger inflammation in response to complement activation.”
The paper relies on this without support.
Findings in amyloidosis and tauopathy mouse models are informative about the mechanisms of microglial function in human AD.
“most published studies in amyloidosis mouse models suggest that depleting microglia and blocking complement pathway activation may have beneficial effects in AD, at least in terms of synapse and neuron loss”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Activated microglia and astrocytes can phagocytize Aβ through multiple receptors to protect neurons,33,34 but failure to clear the aggregates leads to persistent chronic inflammation and the release of a variety of proinflammatory and toxic products, including cytokines, chemokines, reactive oxygen species (ROS) and nitric oxide (NO), which amplify immune responses and lead to neurotoxicity.35”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [35]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Especially, the interaction of microglia within the complex brain microenvironment of AD (e.g. neurons, astrocytes and amyloid-β plaques) is still not well explored.11, 12”
From Acoustofluidic assembly of 3D neurospheroids to model Alzheimer's disease (2020) · cites this paper as [12]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In the brain, PLCγ2 is primarily expressed by microglia, where it serves as an important signaling node downstream of TREM2 and CD33 (19, 20), both also AD risk genes (21–23).”
From Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain (2023) · cites this paper as [20]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Within the brain, PLCγ2 is primarily but not exclusively expressed in microglia, where it serves as an important signaling node downstream of TREM2 and CD33 [31, 32], both also AD risk genes [33–35].”
From PLCγ2 deficiency compromises systemic immune tolerance and erodes myelin homeostasis while enhancing oxidative metabolism in the mouse brain (2026) · cites this paper as [32]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Conversely, extensive microglial activation promotes chronic neuroinflammation, which causes neuronal damage and thus is a major player in AD pathogenesis alongside β-amyloid aggregation and hyperphosphorylated tau deposition [4].”
From The protective PLCγ2-P522R variant mitigates Alzheimer’s disease-associated pathologies by enhancing beneficial microglial functions (2025) · cites this paper as [4]
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“APOE ε4 is known to disrupt lipid homeostasis and immune response and to cause mitochondrial dysfunction [31–34]”
From Protective PLCG2 variants associate with a delayed onset of Alzheimer’s disease among heterozygous APOE ε4 carriers (2026) · cites this paper as [31]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Transcriptionally, the DAM signature includes downregulation of genes expressed in homeostatic microglia such as CX3CR1 and P2RY12 and upregulation of genes including APOE, AXL, SPP1 and TREM2, as well as major histocompatibility complex class II (MHC-II), a gene essential for the initiation of antigen-specific immune response [27–29].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [29]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Likewise, microglia, the brain-resident immunocompetent macrophages, also recognize Aβ oligomers via receptors such as CD36, toll-like receptor 4 (TLR4) and TLR6 and triggering receptor expressed on myeloid cells 2 (TREM2), acquiring specific AD-associated phenotypes [14,15,16].”
From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [16]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In addition, several studies showed the paramount role of microglial cells in maintaining tissue homeostasis and keeping the extracellular space clean of β-amyloid (Aβ), thereby preventing AD [27].”
From Oral Microbially-Induced Small Extracellular Vesicles Cross the Blood–Brain Barrier (2024) · cites this paper as [27]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Besides neurons, glia and in particular microglia are now considered a second brain cell type phenotypic of AD’s cellular pathologies (Salter and Stevens, 2017; Hansen et al., 2018; Takatori et al., 2019; Streit et al., 2020), which play a dominant role in modulating how the brain responds to AD’s triggering neuronal-based pathologies.”
From The neuronal retromer can regulate both neuronal and microglial phenotypes of Alzheimer's disease (2022) · cites this paper as Hansen et al., 2018
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“The microglial response to amyloid plaques in AD can range from neuroprotective to neurotoxic2.”
From Lymphoid gene expression supports neuroprotective microglia function (2025) · cites this paper as [2]
The cited source says what the claim attributes to it.
In the citing paper
“Human genetic studies suggest that reduced SPI1 expression may be protective, whereas experimental data indicate that excessive PU.1 suppression can impair essential microglial functions.”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [12]
The cited source says what the claim attributes to it.
In the citing paper
“in disease, these same capacities can become either protective or damaging depending on context, timing, and molecular state [10,11,12].”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [12]
The cited source says what the claim attributes to it.
In the citing paper
“This older binary language is now considered too limited.”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [12]
The cited source says what the claim attributes to it.
In the citing paper
“The key implication was that Alzheimer’s risk could be influenced not only by coding changes in immune genes, but also by regulatory variants that alter how strongly a myeloid transcription factor is expressed.”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [12]
The cited source says what the claim attributes to it.
In the citing paper
“A common protective haplotype associated with lower SPI1 expression was reported to delay Alzheimer’s disease onset, suggesting that reduced PU.1 abundance in myeloid cells may be beneficial under some disease-relevant conditions.”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [12]
The cited source says what the claim attributes to it.
In the citing paper
“Although microglia are heavily implicated in the pathogenesis of AD [118]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [118]
The cited source says what the claim attributes to it.
In the citing paper
“Microglial cells represent the main innate immune population residing in the central nervous system (CNS). Through the clearance of pathogens, dead cells, and protein aggregates such as A β , they play a critical role in CNS immune surveillance and the preservation of tissue homeostasis [33,34].”
From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [34]
The cited source says what the claim attributes to it.
In the citing paper
“microglia dysfunction has also been suspected to be involved in AD through modulating Aβ aggregation/degradation [45].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [45]
In the citing paper
“Microglia are increasingly recognized as a central cell type contributing to the etiology of AD32.”
From A computational tool (H-MAGMA) for improved prediction of brain-disorder risk genes by incorporating brain chromatin interaction profiles (2020) · cites this paper as [32]
In the citing paper
“Inappropriate control of the classical complement cascade causes unresolvable inflammation and disease (Hong et al. , 2016; Hansen, Hanson and Sheng, 2018; Morgan, 2018).”
From Spatial Transcriptomics and In Situ Sequencing to Study Alzheimer’s Disease (2020) · cites this paper as Hansen, Hanson and Sheng, 2018
In the citing paper
“genetic and histological findings suggest that human AD involves impairments in microglial activation (Hansen et al., 2018; Streit et al., 2009).”
From Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation (2020) · cites this paper as Hansen et al., 2018
In the citing paper
“In neurodegenerative state, microglia can enhance neuroinflammation leading to more cell deaths [6, 8].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [8]
In the citing paper
“Importantly, the capability of astrocytes and microglia to internalize and degrade Aβ (Guénette, 2003; Hansen et al., 2018) is strictly correlated with their aberrant activation during the AD progression (Bates et al., 2009; Ries and Sastre, 2016).”
From Exploring the Therapeutic Potential of Phytochemicals in Alzheimer’s Disease: Focus on Polyphenols and Monoterpenes (2022) · cites this paper as Hansen et al., 2018
In the citing paper
“However, in a reactionary or dystrophic state, microglia also contribute to the pathogenesis of various NDs and post-TBI syndromes [43–45].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [43]
In the citing paper
“Discoveries over the last decade suggest that many, perhaps even a majority, of the genes contributing risk to AD are expressed primarily by microglia (1, 2), the resident myeloid cells of the brain parenchyma.”
From The Transcriptional Landscape of Microglial Genes in Aging and Neurodegenerative Disease (2019) · cites this paper as [2]
Citations
Cites
1 retracted
Microglia-dependent synapse loss in type I interferon-mediated lupus
Bialas, A. R., Presumey, J., Das, A., van der Poel, C. E., Lapchak, P. H., Mesin, L., Victora, G., Tsokos, G. C., Mawrin, C., Herbst, R., et al. (2017) · Nature · doi:10.1038/nature22821 · Cited by 197 · cited 2×
“…molecules in the brain, is present in Aβ plaques (Namba et al., 1991; Wisniewski and Frangione, 1992; Zhan et al., 1995) and contributes to both the clearance and the amyloid deposition of Aβ peptide (Bales et al., 1997a; DeMattos et al., 2004; Bien-Ly et al., 2012; Holtzman et al., 2012).”
BackgroundRetractedAmyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., & Pericak-Vance, M. A. (1993) · Science · doi:10.1126/science.8346443 · Cited by 9,429
Neurotoxic reactive astrocytes are induced by activated microglia
Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., Bennett, M. L., Münch, A. E., Chung, W.-S., Peterson, T. C., et al. (2017) · Nature · doi:10.1038/nature21029 · Cited by 7,971
The amyloid hypothesis of Alzheimer's disease at 25 years
Selkoe, D. J., & Hardy, J. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201606210 · Cited by 6,164 · cited 1×
“Knockout or inhibition of C3, which should block all pathways of complement activation, is also reported to provide neuroprotection (Shi et al., 2015, 2017a; Hong et al., 2016; for different results, see Wyss-Coray et al., 2002; Maier et al., 2008), though it appears to increase amyloid burden…”
BackgroundResting microglial cells are highly dynamic surveillants of brain parenchyma in vivo
Nimmerjahn, A., Kirchhoff, F., & Helmchen, F. (2005) · Science · doi:10.1126/science.1110647 · Cited by 5,827 · cited 1×
“Involved in chemotactic polarization and migration of macrophages (Okigaki et al., 2003).”
BackgroundA Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease
Keren-Shaul, H., Spinrad, A., Weiner, A., Matcovitch-Natan, O., Dvir-Szternfeld, R., Ulland, T. K., David, E., Baruch, K., Lara-Astaiso, D., Toth, B., et al. (2017) · Cell · doi:10.1016/j.cell.2017.05.018 · Cited by 5,493 · cited 6×
“Analyzing activated microglia as a separate population or by single-cell RNA-sequencing also reveals subtle (two- to threefold) increases in Trem2 and Tyrobp mRNAs (Kamphuis et al., 2016; Keren-Shaul et al., 2017; Yin et al., 2017).”
BackgroundMethodInfluentialFate Mapping Analysis Reveals That Adult Microglia Derive from Primitive Macrophages
Ginhoux, F., Greter, M., Leboeuf, M., Nandi, S., See, P., Gokhan, S., Mehler, M. F., Conway, S. J., Ng, L. G., Stanley, E. R., et al. (2010) · Science · doi:10.1126/science.1194637 · Cited by 5,175 · cited 1×
“Their homeostasis and self-renewal is maintained by several factors, including TGF-β and CSF1R signaling (Ginhoux et al., 2010; Butovsky et al., 2014; Elmore et al., 2014).”
BackgroundHypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade
Jack, C. R., Knopman, D. S., Jagust, W. J., Shaw, L. M., Aisen, P. S., Weiner, M. W., Petersen, R. C., & Trojanowski, J. Q. (2010) · The Lancet Neurology · doi:10.1016/s1474-4422(09)70299-6 · Cited by 4,806 · cited 1×
“Amyloid plaques appear a decade or two before clinical symptoms of AD, but it is tau pathology and synapse loss that correlate best with cognitive impairment during disease progression (Jack et al., 2010).”
BackgroundComplement factor H polymorphism in age-related macular degeneration
Klein, R. J., Zeiss, C., Chew, E. Y., Tsai, J.-Y., Sackler, R. S., Haynes, C., Henning, A. K., SanGiovanni, J. P., Mane, S. M., Mayne, S. T., et al. (2005) · Science · doi:10.1126/science.1109557 · Cited by 4,492
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Items 801–900 of 1,017
Hua, J., Paco, E. G. D., Linck, N., Maurice, T., Desrumaux, C. M., Manoury, B., Rassendren, F., & Ulmann, L. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-04784-x · Cited by 22
ALZHEIMER’S DISEASE AND ITS RELATIONSHIP WITH THE MICROBIOTA-GUT-BRAIN AXIS
Faulin, T. D. E. S., & Estadella, D. (2023) · Arquivos de Gastroenterologia · doi:10.1590/s0004-2803.202301000-17 · Cited by 25
“However, it is proposed that the chronic activation of microglia leads to a pro-inflammatory state inducing the secretion of neurotoxic cytokines that damage neurons and stimulate the development of AD (14) .”
BackgroundModulation of microRNAs through Lifestyle Changes in Alzheimer’s Disease
Pinto-Hernandez, P., Castilla-Silgado, J., Coto-Vilcapoma, A., Fernández-Sanjurjo, M., Fernández-García, B., Tomás-Zapico, C., & Iglesias-Gutiérrez, E. (2023) · Nutrients · doi:10.3390/nu15173688 · Cited by 22
“Extracellularly, microglia collect and clean up soluble Aβ species, phagocyte insoluble fibrillar Aβ deposits, and induce both the activated microglia state and the trapping of amyloid plaques [8].”
BackgroundGamache, J., Gingerich, D., Shwab, E. K., Barrera, J., Garrett, M. E., Hume, C., Crawford, G. E., Ashley-Koch, A. E., & Chiba-Falek, O. (2023) · Cell & Bioscience · doi:10.1186/s13578-023-01120-5 · Cited by 20
“The importance of microglia in AD has been previously established [77–79].”
BackgroundYe, L., Hu, M., Mao, R., Yi, T., Sun, M., Jia, J., Xu, S., Liu, Y., Zhu, X., Xu, Y., et al. (2023) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14555 · Cited by 20
“30,31 Microglial activation-mediated neuroinflammation plays an important role in the pathogenesis of AD.”
BackgroundXu, J., Gou, S., Huang, X., Zhang, J., Zhou, X., Gong, X., Xiong, J., Chi, H., & Yang, G. (2023) · Current Alzheimer Research · doi:10.2174/0115672050280894231214063023 · Cited by 21
Jin, J., Zhang, H., Lu, Q., Tian, L., Yao, S., Lai, F., Liang, Y., Liu, C., Lu, Y., Tian, S., et al. (2024) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-24-00303 · Cited by 20
Protective Effects of Polydatin Against Dementia-Related Disorders
Tang, K. S. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200611144825 · Cited by 29
Pathogenesis, Animal Models, and Drug Discovery of Alzheimer’s Disease
Xia, Z.-D., Ma, R.-X., Wen, J.-F., Zhai, Y.-F., Wang, Y.-Q., Wang, F.-Y., Liu, D., Zhao, X.-L., Sun, B., Jia, P., et al. (2023) · Journal of Alzheimer's Disease · doi:10.3233/jad-230326 · Cited by 19
“There is evidence that abnormal changes in microglia is associated with AD [73].”
Unraveling the dual nature of brain CD8+ T cells in Alzheimer’s disease
Hu, D., & Weiner, H. L. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00706-y · Cited by 19
“As AD advances, microglia may gradually lose their ability to eliminate these plaques effectively, and, in turn, begin to generate inflammatory mediators that could potentially expedite the progression of Aβ plaque accumulation [4].”
BackgroundMagnussen, J. H. (2025) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.70061 · Cited by 21
Serna-Orozco, M. F., Mosquera, M., & García‐Perdomo, H. A. (2025) · NeuroMolecular Medicine · doi:10.1007/s12017-025-08866-w · Cited by 23
Li, H., Gao, J., Chang, Y., Li, K., Wang, L., Ju, C., & Zhang, F. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2021.107726 · Cited by 19
A multifaceted role of progranulin in regulating amyloid-beta dynamics and responses
Du, H., Wong, M. Y., Zhang, T., Santos, M. N., Hsu, C., Zhang, J., Yu, H., Luo, W., & Hu, F. (2021) · Life Science Alliance · doi:10.26508/lsa.202000874 · Cited by 20
“Microglia-mediated inflammation (Aldana, 2019; Colonna and Butovsky, 2017; Hammond et al., 2019; Hansen et al., 2018; Hickman et al., 2018) and endo-lysosomal dysfunction (Bajaj et al.”
BackgroundProtective Role of Microglia on Neuronal Survival after Exposure to Amyloid Beta
Lee, S., & Choi, W. (2022) · Chonnam Medical Journal · doi:10.4068/cmj.2022.58.1.13 · Cited by 19
Yang, X., Zu, H., Zhao, Y., & Yao, K. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.766410 · Cited by 19
Sleep Disturbance and Alzheimer’s Disease: The Glial Connection
Sunkaria, A., & Bhardwaj, S. (2022) · Neurochemical Research · doi:10.1007/s11064-022-03578-0 · Cited by 19
Mishra, S., Kinoshita, C., Axtman, A. D., & Young, J. E. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.824956 · Cited by 16
“When microglia are activated in AD they can release pro-inflammatory cytokines, such as IL-6 and IL-1 β , which can exacerbate other pathologies (Hansen et al., 2018).”
BackgroundAyyubova, G. (2023) · European Journal of Neuroscience · doi:10.1111/ejn.15914 · Cited by 21
Zhou, W., Lei, B., Yang, C., Silva, M., Xing, X., Yu, H., Lu, J., & Zheng, W. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24065259 · Cited by 20
“However, microglia overactivation triggers the release of different pro-inflammatory factors, contributing to the installation of a neuroinflammatory state in AD brains [56,57].”
BackgroundBettendorff, L. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241411296 · Cited by 21
“This process is likely to play an important role in neurodegenerative processes [80].”
BackgroundMass‐Guided Single‐Cell MALDI Imaging of Low‐Mass Metabolites Reveals Cellular Activation Markers
Cairns, J. L., Huber, J., Lewen, A., Jung, J., Maurer, S. J., Bausbacher, T., Schmidt, S., Levkin, P. A., Sévin, D. C., Göpfrich, K., et al. (2024) · Advanced Science · doi:10.1002/advs.202410506 · Cited by 21
Zhang, F., Wu, H., Jin, Y., & Zhang, X. (2018) · World Neurosurgery · doi:10.1016/j.wneu.2018.09.037 · Cited by 19
Alzheimer’s disease: Key developments support promising perspectives for therapy
Meldolesi, J. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104316 · Cited by 19
Glibenclamide modulates microglial function and attenuates Aβ deposition in 5XFAD mice.
Ju, Y.-J., Kim, N., Min, S.-G., Jeon, S., Lee, D., Do, J., Ryu, J.-S., & Lee, J. K. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173416 · Cited by 17
Zhang, J., Boska, M. D., Zheng, Y., Liu, J., Fox, H. S., & Xiong, H. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02142-x · Cited by 19
Tau and Amyloid beta causes microglial activation in Alzheimer’s disease
Chinnathambi, S., Adithyan, A., Chandrashekar, M., & Rangappa, N. (2025) · Advances in clinical chemistry · doi:10.1016/bs.acc.2025.06.002 · Cited by 19
Pan, T.-T., Sun, Y., Shi, Y.-F., Zhao, M., Khan, N. U., Chen, H., Ji, W., Li, J., Han, L., & Ma, Q. (2025) · Alzheimer s Research & Therapy · doi:10.1186/s13195-025-01840-5 · Cited by 19
cGAS-STING signaling in Alzheimer's disease: Microglial mechanisms and therapeutic opportunities
Fazal, F., Dar, N. J., Ahamad, S., Khan, S., Bano, N., Saha, S., Nazir, A., & Bhat, S. A. (2026) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2025.101444 · Cited by 21
Unraveling Alzheimer’s Disease Using Drosophila
Yeates, C. J., Sarkar, A., Kango‐Singh, M., & Singh, A. (2019) · Springer eBooks · doi:10.1007/978-981-13-2218-1_9 · Cited by 18
Lennon, J. C. (2020) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-200190 · Cited by 18
“The observed microglial dysregulation during stressful events is that which is implicated in AD pathogenesis due to the preferential expression of microglia by identified risk genes [22].”
BackgroundMicroglia Biomarkers in Alzheimer’s Disease
Zhang, P., Hu, H., Tan, L., & Yu, J. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02348-3 · Cited by 19
Wang, M., Fang, L., Liu, T., Chen, X., Zheng, Y. H., Zhang, Y., Chen, S., & Li, Z. (2021) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2021.109489 · Cited by 19
Hypoxia/ischemia impairs CD33 (Siglec-3)/TREM2 signaling: Potential role in Alzheimer's pathogenesis
Salminen, A., Kaarniranta, K., & Kauppinen, A. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.105186 · Cited by 20
“Recent genetic and molecular studies have emphasized the crucial role of microglia and a low-grade neuroinflammation in the pathogenesis of AD (Hansen et al., 2018; Leng and Edison, 2021).”
BackgroundWiatrak, B., Jawień, P., Matuszewska, A., Szeląg, A., & Kubis-Kubiak, A. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.112880 · Cited by 17
Gao, X., Cao, Z., Tan, H., Li, P., Su, W., Wan, T., & Guo, W. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.903472 · Cited by 18
“As the disease continues to progress, activated microglia mediate the phagocytosis of synapses by expressing C3a, C5a and C3R (C means Complement, R means receptor), leading to synaptic deficits (Hansen et al., 2018).”
BackgroundDeletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways
Ibanez, K. R., McFarland, K. N., Phillips, J., Allen, M., Lessard, C. B., Zobel, L., De La Cruz, E. G., Shah, S., Vo, Q., Wang, X., et al. (2022) · Alzheimer's Research & Therapy · doi:10.1186/s13195-022-01044-1 · Cited by 18
“Recent genetic and transcriptomic data have highlighted the involvement of immune signaling processes in AD pathogenesis [4].”
BackgroundWendt, S., Johnson, S., Weilinger, N. L., Groten, C., Sorrentino, S., Frew, J., Yang, L., Choi, H. B., Nygaard, H. B., & MacVicar, B. A. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102448 · Cited by 20
“Microglia, the primary immune cells of the brain express many AD risk genes [16] and accumulate around Aβ plaques in human AD patients and in AD mouse models.”
BackgroundLi, K., Ran, B., Wang, Y., Liu, L., & Li, W. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.999061 · Cited by 18
“The phenotypic transition of microglia is a dynamic process during the development and progression of AD (Yenari et al., 2010; Chu et al., 2018; Hansen et al., 2018).”
BackgroundFerrisi, R., Gado, F., Polini, B., Ricardi, C., Mohamed, K. A., Stevenson, L., Ortore, G., Rapposelli, S., Saccomanni, G., Pertwee, R. G., et al. (2022) · Frontiers in Chemistry · doi:10.3389/fchem.2022.984069 · Cited by 18
“Taking into account that the inflammatory process in microglial cells supports the onset and progression of several neurodegenerative and psychiatric disorders (Nakagawa and Chiba, 2014; Hansen et al., 2018; Haukedal and Freude 2019; Ho 2019), we decided to investigate the antiinflammatory properties of novel CB2R lig…”
BackgroundDisturbance of REM sleep exacerbates microglial activation in APP/PS1 mice
Liu, S., Meng, Y., Wang, N., Lei, Q., He, L., Hong, X., & Li, Z. (2023) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2023.107737 · Cited by 19
Microglia secrete distinct sets of neurotoxins in a stimulus-dependent manner
Bernath, A. K., Murray, T. E., Yang, S., Gibon, J., & Klegeris, A. (2023) · Brain Research · doi:10.1016/j.brainres.2023.148315 · Cited by 20
Butler, T., Wang, X. H., Chiang, G. C.-Y., Li, Y., Zhou, L., Xi, K., Wickramasuriya, N., Tanzi, E. B., Spector, E. B., Özşahin, İ., et al. (2023) · American Journal of Neuroradiology · doi:10.3174/ajnr.a7903 · Cited by 18
REST in the Road Map of Brain Development
Lam, X.-J., Maniam, S., Cheah, P.-S., & Ling, K. (2023) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-023-01394-w · Cited by 20
Alzheimer’s disease: an axonal injury disease?
Liang, D., & Zhang, Z. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1264448 · Cited by 21
“These variants affect the stability of TREM2, impair its phagocytic ability, and alter its affinity for APOE4, clusterin (ApoJ), low-density lipoprotein, and A β (Hansen et al., 2018).”
Pradhan, A. K., Neumüller, T., Klug, C., Fuchs, S., Schlegel, M., Ballmann, M., Tartler, K. J., Pianos, A., Garcia, M. S., Lière, P., et al. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02630-z · Cited by 19
“However, in AD, the microglia have been shown to have an increased expression of in fl ammatory markers which include CD36, CD14, CD11c, MHCII, and iNOS [49 – 51].”
BackgroundA Review on the Protective Effects of Probiotics against Alzheimer’s Disease
Mishra, V., Yadav, D., Solanki, K. S., Koul, B., & Song, M. (2023) · Biology · doi:10.3390/biology13010008 · Cited by 20
“Microglia creates a barrier of defense surrounding amyloid deposits, preventing fresh A β from adhering to already-formed plaques [109].”
BackgroundBellio, T. A., Laguna-Torres, J. Y., Campion, M. S., Chou, J., Yee, S., Blusztajn, J. K., & Mellott, T. J. (2024) · PLoS ONE · doi:10.1371/journal.pone.0297289 · Cited by 23
Genetic diversity promotes resilience in a mouse model of Alzheimer's disease
Soni, N., Hohsfield, L. A., Tran, K. M., Kawauchi, S., Walker, A., Javonillo, D. I., Phan, J., Matheos, D. P., Cunha, C. D., Uyar, A., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.13753 · Cited by 17
“46 Given the key role of microglia in A β -related pathology and the significant differences in A β plaque deposition between the different 5x-CC strains, we next stained mouse brains for ThioS and IBA1, a microglial cell marker, and evaluated microglial density in both WT-and 5x-CC strains at 4…”
MethodLi, Y., Zhou, C., Liu, H., Cai, T., & Fan, H. (2024) · Biomolecules · doi:10.3390/biom14030312 · Cited by 20
“…2, which concludes that the imbalance of beneficial and pathogenic OMVs enhances the neuroinflammation of neurodegenerative disorders mediated by the gut–brain axis, suggesting a key role of not only mammalian cell-derived EVs but also bacteria-derived EVs in the development of neurodegeneration.”
BackgroundMolecular mechanisms implicated in protein changes in the Alzheimer’s disease human hippocampus
Nguyen, H. D., Kim, W.-K., & Vu, G. H. (2024) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2024.111930 · Cited by 17
“The presence of NFTs and amyloid-beta plaques, which are components of AD neuropathology, is linked to the process of neurodegeneration and the activation of microglial cells (Hansen et al., 2018).”
BackgroundThe crosstalk between extracellular matrix proteins and Tau
Chinnathambi, S., & Desale, S. E. (2024) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2024.04.002 · Cited by 19
Ritter, A. R., Cummings, J. L., Nance, C., & Miller, J. B. (2018) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1016/j.trci.2018.06.006 · Cited by 19
Evaluating the Role of Microglial Cells in Clearance of Aβ from Alzheimer’s Brain
Manchikalapudi, A. L., Chilakala, R. R., Kalia, K., & Sunkaria, A. (2019) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.8b00627 · Cited by 18
Wakulik, K., Wiatrak, B., Szczukowski, Ł., Bodetko, D., Szandruk-Bender, M., Dobosz, A., Świątek, P., & Gąsiorowski, K. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21072575 · Cited by 19
“Increased expression of proinflammatory mediators such as cytokines and chemokines (IL-1β, IL-6, TNF-α), complement components (C1q, C3a, C3b), and acute-phase proteins opsonising β-amyloid deposits are observed [10].”
BackgroundThe Role of TREML2 in Alzheimer’s Disease
Wang, S., Gong, P., Yan, E., Zhang, Y., & Jiang, T. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-200406 · Cited by 18
“In the context of AD,microgliacanbeactivatedbyA (cid:2) andplaysadual roleduringdiseaseprogression:ononeside,activated microgliaparticipatesintheclearanceofA (cid:2) deposition through its phagocytic activity [38].”
Anwar, M. M., Badawi, A. M., & Eltablawy, N. A. (2020) · eNeurologicalSci · doi:10.1016/j.ensci.2020.100290 · Cited by 20
“2 general systemic body injuries or infection [11,12].”
BackgroundYang, W., Zhang, Y., Li, Y., Nie, Y., Liang, J., Liu, Y., Liu, J., Zhang, Y., Song, C., Qian, Z., et al. (2020) · Chemistry & Biodiversity · doi:10.1002/cbdv.202000055 · Cited by 18
Guo, Y., Zhao, J., Liu, X., Lu, P., Liang, F., Wang, X., Wu, J., & Hai, Y. (2025) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-024-10165-3 · Cited by 17
“The dual impact of microglia-mediated neuroinflammation in AD progression has been widely recognized (Hansen et al. 2018).”
Alzheimer’s disease basics: we all should know
Das, S. K. (2025) · Neurological Research · doi:10.1080/01616412.2025.2529560 · Cited by 19
“Moreover, astrocytes control synaptic transmission and aid in the spatiotemporal integration of various synaptic inputs [42,43].”
Guo, F., Sheng, Z.-H., Fu, Y., Wang, Z., Xue, R., Tan, M., Tan, M.-S., & Wang, Z.-T. (2025) · Translational Psychiatry · doi:10.1038/s41398-025-03458-5 · Cited by 21
Jin, Z., Lu, Y., Tang, H., & Cui, H. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70472 · Cited by 24
“107 110 Furthermore, tau pathology also intensifies glial activity, prompting innate immune cell activation and the release of both pro-and anti-inflammatory molecules 111 that create a self-amplifying neuroinflammation cycle.”
Effects of exercise on neuroinflammation in age-related neurodegenerative disorders
Su, Y., & Su, Z. (2025) · European journal of medical research · doi:10.1186/s40001-025-03165-3 · Cited by 22
“This further stimulates immune reactions and causes damage to neurons [60].”
Shen, J., Yang, B., Xie, Z., Wu, H., Zheng, Z., Wang, J., Wang, P., Zhang, P., Li, W., Ye, Z., et al. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.639527 · Cited by 15
Human Monocytes Plasticity in Neurodegeneration
Savinetti, I., Papagna, A., & Foti, M. (2021) · Biomedicines · doi:10.3390/biomedicines9070717 · Cited by 19
B Lymphocytes in Alzheimer’s Disease—A Comprehensive Review
Plantone, D., Pardini, M., Locci, S., Nobili, F. M., & Stefano, N. D. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-220261 · Cited by 19
“On the other hand, via a complement-dependent mechanism, microglia can also be responsible for synapse loss by engulfment of synapses and can secrete inflammatory mediators that can directly or indirectly (via astrocytes) harm neurons [20].”
An overview on microglial origin, distribution, and phenotype in Alzheimer's disease
Islam, R., Choudhary, H. H., Rajan, R. G., Vrionis, F. D., & Hanafy, K. A. (2022) · Journal of Cellular Physiology · doi:10.1002/jcp.30829 · Cited by 18
“At late stages of AD, microglia may paradoxically contribute to the disease by releasing pro ‐ inflammatory cytokines in response to Ab deposition (Hansen et al., 2018; Hickman et al., 2018).”
BackgroundDai, Y., Liu, S., Chen, J., Liu, L., Zhou, C., & Zuo, Y. (2022) · Neuroscience · doi:10.1016/j.neuroscience.2022.09.004 · Cited by 19
Identifying an Optimal Neuroinflammation Treatment Using a Nanoligomer Discovery Engine
Sharma, S., Borski, C., Hanson, J. L., Garcia, M. A., Link, C. D., Hoeffer, C. A., Chatterjee, A., & Nagpal, P. (2022) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.2c00365 · Cited by 15
Self-citationImmunity orchestrates a bridge in gut-brain axis of neurodegenerative diseases
Cheng, Y., Chen, C., & Zhang, F. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101857 · Cited by 19
Flavonoids as Promising Multitarget Agents in Alzheimer’s Disease Therapy
Lima, E., Rauter, A. P., & Medeiros, J. (2023) · Applied Sciences · doi:10.3390/app13084651 · Cited by 17
Association between APOE genotype and microglial cell morphology
Kloske, C. M., Gearon, M. D., Weekman, E. M., Rogers, C. B., Patel, E., Bachstetter, A. D., Nelson, P. T., & Wilcock, D. M. (2023) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlad031 · Cited by 17
Ciccone, L., Nencetti, S., Rossello, A., & Orlandini, E. (2023) · Pharmaceuticals · doi:10.3390/ph16071036 · Cited by 18
“Even if the molecular mechanism of AD is not completely known, studies report that Aβ1–42 and NFTs can trigger the neuroinflammatory process through the activation of microglia, astrocytes, and the induction of proinflammatory cytokines [89,90].”
BackgroundLiu, Q., Contreras, A. J., Afaq, M. S., Yang, W., Hsu, D. K., Russell, M., Lyeth, B. G., Zanto, T. P., & Zhao, M. (2023) · Cell & Bioscience · doi:10.1186/s13578-023-01085-5 · Cited by 19
Shafer, C. C., & Neumann, E. K. (2024) · Frontiers in Chemistry · doi:10.3389/fchem.2024.1334209 · Cited by 17
“…differences in individual cells within the native microenvironment have great applications in the study of disease states such as AD, where activated microglia are a known hallmark of disease but have both bene fi cial and toxic effects over time that are not fully understood (Hansen et al., 2017).”
BackgroundAn Epigenetic Manifestation of Alzheimer's Disease: DNA Methylation
Feng, B., Zheng, J., Cai, Y., Han, Y., Han, Y., Wu, J., Feng, J., & Zheng, K. (2024) · Actas Españolas de Psiquiatría · doi:10.62641/aep.v52i3.1595 · Cited by 19
Guo, Y., Xu, S., Pan, X., Xin, W., Cao, W., Ma, W., Li, L., Shen, Q., & Li, Z. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.112493 · Cited by 17
Mulumba, J., Duan, R., Luo, B., Wu, J., Sulaiman, M., Wang, F., & Yang, Y. (2025) · Exploration of neuroscience · doi:10.37349/en.2025.100675 · Cited by 23
Hemonnot-Girard, A.-L., Valverde, A., Hua, J., Delaygue, C., Linck, N., Maurice, T., Rassendren, F., & Hirbec, H. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.10.021 · Cited by 17
Advances in Proteomics Allow Insights Into Neuronal Proteomes
Fingleton, E., Li, Y., & Roche, K. W. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.647451 · Cited by 17
Nihonmatsu-Kikuchi, N., Yu, X., Matsuda, Y., Ozawa, N., Ito, T., Satou, K., Kaname, T., Iwasaki, Y., Akagi, A., Yoshida, M., et al. (2021) · Communications Biology · doi:10.1038/s42003-021-02404-7 · Cited by 16
Rosenthal, S. B., Wang, H., Shi, D., Liu, C., Abagyan, R. A., McEvoy, L. K., & Chen, C. (2022) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1009903 · Cited by 18
“Given that these clustered genes are associated with AD risk in GWAS, up-regulated in AD, and preferentially expressed in cells with close etiological relationship with AD, these findings suggest that the genomic and transcriptional alterations in this cluster likely play a causal role in AD pathogenesis, rather than…”
Transcorneal electrical stimulation enhances cognitive functions in aged and 5XFAD mouse models
Yu, W. S., Aquili, L., Wong, K. H., Lo, A., Chan, L. L. H., Chan, Y., & Lim, L. W. (2022) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14850 · Cited by 17
Microglia activation linking amyloid-β drive tau spatial propagation in Alzheimer's disease
Wang, Q., & Xie, C. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.951128 · Cited by 20
“Whymicroglial activation could influence the distribution of tau? In the pathological progression of AD, different species of Aβ aggregates, tau oligomers and fibrils, and damaged neurons could induce microglia activation and the production of proinflammatory cytokines and chemokines, all of which could lead to neuron…”
BackgroundHassan, M., Shahzadi, S., Alashwal, H., Zaki, N., Seo, S., & Moustafa, A. A. (2018) · Neurological Sciences · doi:10.1007/s10072-018-3430-2 · Cited by 17
Tolédano, A., Rodríguez‐Casado, A., Álvarez, M., & Toledano‐Díaz, A. (2024) · Brain Sciences · doi:10.3390/brainsci14111101 · Cited by 19
Primary cilia-mediated regulation of microglial secretion in Alzheimer’s disease
Yeo, S., Jang, J., Jung, H. J., Lee, H., & Choe, Y. (2023) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2023.1250335 · Cited by 18
“AD risk genes such as TREM2, ABCA7, CD33, MS4A6A, CR1, INPP5D, BIN1, PICALM, EPHA1, CD2AP, SORL1, and RIN3 are tightly linked to A β clearance via the endo-lysosomal pathway (Hansen et al., 2018; Lambert et al., 2022).”
The role of inhibitory immune checkpoint receptors in the pathogenesis of Alzheimer’s disease
Salminen, A. (2024) · Journal of Molecular Medicine · doi:10.1007/s00109-024-02504-x · Cited by 16
Gao, R., Gao, Y., Su, W., & Wang, R. (2025) · Aging and Disease · doi:10.14336/ad.2024.1629 · Cited by 18
“AD accounts for 60 – 70% of dementia cases and is defined by its hallmark amyloid-beta (Aβ) plaques and hyperphosphorylated tau protein tangles [59,135,136].”
Gonul, C. P., Karaçiçek, B., & Genç, Ş. (2025) · Developmental Neurobiology · doi:10.1002/dneu.22984 · Cited by 17
Emerging Role of Oligodendrocytes Malfunction in the Progression of Alzheimer's Disease
Tylek, K., & Basta‐Kaim, A. (2025) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-025-10236-z · Cited by 19
“However, in AD, dysfunctional crosstalk with microglia leads to sustained neuroinflammation and oxidative stress (Hansen et al. 2018).”
The Gut-Brain Axis in Alzheimer’s Disease: Exploring Microbial Influences and Therapeutic Strategies
Mustafa, M. A., Vadia, N., Varma, P., Al‐Shaker, H., Mohanty, B., Dhyani, A., Kaur, I., Chauhan, A. S., & Garg, G. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-05474-4 · Cited by 18
“Microglial activation is another key feature of AD pathology, with microglia playing an essential role in the phagocytosis of both soluble and fibrillar Aβ deposits [151].”
Wang, Q., Liu, L., Guan, H., Zhou, Y., & Li, Q. (2021) · Pharmaceutical Biology · doi:10.1080/13880209.2021.1941132 · Cited by 16
Ali, M., Huarte, O. U., Heurtaux, T., Garcia, P., Rodriguez, B. P., Grzyb, K., Halder, R., Skupin, A., Buttini, M., & Glaab, E. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-02985-2 · Cited by 27
“A number of systems biology studies have highlighted the protective functions of microglia and proposed that a loss of microglial cell function may involve a loss of neuroprotection that could contribute to neurodegeneration [81, 82].”
BackgroundLiu, J., Xie, Y., Lu, Y., Zhao, Z., Zhuang, Z., Yang, L., Huang, H., Li, H., Mao, Z., Pi, S., et al. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-221205 · Cited by 16
“The proliferation and activation of microglia in the brain, concentrated around amyloid plaque, is a prominent feature of AD [73].”
Ennerfelt, H. E., Holliday, C., Shapiro, D. A., Zengeler, K. E., Bolte, A. C., Ulland, T. K., & Lukens, J. R. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2303760120 · Cited by 16
Wang, Y., Wu, T. Z., Tsai, M., Rezzonico, M. G., Abdel‐Haleem, A. M., Xie, L., Gandham, V. D., Ngu, H., Stark, K. L., Glock, C., et al. (2023) · eLife · doi:10.7554/elife.83451 · Cited by 16
“83451 2 of 29 may facilitate beneficial functions, such as clearance of amyloid plaques, in the early stages of AD, chronic microglia activation could contribute to disease progression via cytokine release and other harmful functions during later stages of disease (Bright et al., 2019; Hansen et al., 2018; Leng and Ed…”
BackgroundMethodSelf-citationHoyer-Kimura, C. H., Hay, M., Konhilas, J. P., Morrison, H. W., Methajit, M., Strom, J. G., Polt, R. L., Salcedo, V., Fricks, J. P., Kalya, A., et al. (2023) · Aging and Disease · doi:10.14336/ad.2023.0928 · Cited by 17
Monoclonal antibody therapy for Alzheimer's disease focusing on intracerebral targets
Gu, X., Long, Q., Qi, Q., Zhou, J., Chen, S., & Wang, L. (2024) · BioScience Trends · doi:10.5582/bst.2023.01288 · Cited by 17
Dong, Q., Fu, H., & Jiang, H. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116880 · Cited by 17
Metadata
- Authors
- Hansen, D. V., Hanson, J. E., & Sheng, M.
- Affiliations
- Genentech (US)
- Corresponding author
- Hansen, David V.
- Sheng, Morgan
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2017-12-01
- Volume
- 217
- Issue
- 2
- Pages
- 459-472
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC5800817
- OpenAlex
- W2774947569
- Semantic Scholar
- fecfe002f9c3883e4476d3ce0a69b874e06566f8
- Cited by
- 1,935
- References
- 184
- Citations by year
- 2026: 208 · 2025: 296 · 2024: 296 · 2023: 305 · 2022: 271 · 2021: 241 · 2020: 173 · 2019: 110 · 2018: 33 · 2017: 2
- FWCI
- 8.39
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Cell Biology (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- Genentech
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- microglia, Alzheimer's disease, microglial activation, amyloid plaques, amyloid-beta, risk genes, synaptic loss, tau pathology, neuroinflammation, astrocyte activation, microglial activation states, neurodegeneration
- MeSH terms
- Alzheimer Disease, Animals, Brain, Humans, Microglia
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