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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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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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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 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
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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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesThe 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
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Not matched
None of the sources cited for this claim have been checked yet.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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×
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BackgroundRetractedAmyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
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BackgroundResting microglial cells are highly dynamic surveillants of brain parenchyma in vivo
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BackgroundA Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease
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BackgroundMethodInfluentialFate Mapping Analysis Reveals That Adult Microglia Derive from Primitive Macrophages
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BackgroundHypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade
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“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
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Synaptic Pruning by Microglia Is Necessary for Normal Brain Development
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BackgroundMechanisms underlying inflammation in neurodegeneration
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“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 (Wyss-Coray et al.”
BackgroundThe Classical Complement Cascade Mediates CNS Synapse Elimination
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“PTK2B/Pyk2 Non–receptor tyrosine kinase; homologue of focal adhesion kinase Activated in microglia by fibrillar Aβ (Combs et al., 1999).”
BackgroundA Lineage of Myeloid Cells Independent of Myb and Hematopoietic Stem Cells
Schulz, C., Perdiguero, E. G., Chorro, L., Szabo-Rogers, H., Cagnard, N., Kierdorf, K., Prinz, M., Wu, B., Jacobsen, S. E. W., Pollard, J. W., et al. (2012) · Science · doi:10.1126/science.1219179 · Cited by 2,578
Variant of TREM2 Associated with the Risk of Alzheimer's Disease
Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P. V., Snaedal, J., Bjornsson, S., Huttenlocher, J., Levey, A. I., Lah, J. J., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211103 · Cited by 2,558 · cited 2×
“5% of most populations) increases the risk of AD approximately threefold (Guerreiro et al., 2013; Jonsson et al., 2013).”
BackgroundIdentification of a unique TGF-β–dependent molecular and functional signature in microglia
Butovsky, O., Jedrychowski, M. P., Moore, C. S., Cialic, R., Lanser, A. J., Gabriely, G., Koeglsperger, T., Dake, B., Wu, P. M., Doykan, C. E., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3599 · Cited by 2,543 · cited 1×
“SORL1 Receptor for vesicular sorting of lipoproteins and various receptors Binds Aβ and directs it to lysosome (Caglayan et al., 2014).”
BackgroundGenomic analysis of reactive astrogliosis
Zamanian, J. L., Xu, L., Foo, L. C., Nouri, N., Zhou, L., Giffard, R. G., & Barres, B. A. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.6221-11.2012 · Cited by 2,404
Schizophrenia risk from complex variation of complement component 4
Sekar, A., Bialas, A. R., de Rivera, H., Davis, A., Hammond, T. R., Kamitaki, N., Tooley, K., Presumey, J., Baum, M., Van Doren, V., et al. (2016) · Nature · doi:10.1038/nature16549 · Cited by 2,394
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“(A) These heat maps depict relative expression levels of GWAS-identified AD risk genes among CNS cell types purified from human (Zhang et al., 2016) or mouse (Srinivasan et al.”
Villemagne, V. L., Burnham, S., Bourgeat, P., Brown, B., Ellis, K. A., Salvado, O., Szoeke, C., Macaulay, S. L., Martins, R., Maruff, P., et al. (2013) · The Lancet Neurology · doi:10.1016/s1474-4422(13)70044-9 · Cited by 2,279
Synapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model
Yoshiyama, Y., Higuchi, M., Zhang, B., Huang, S.-M., Iwata, N., Saido, T. C., Maeda, J., Suhara, T., Trojanowski, J. Q., & Lee, V. M.-Y. (2007) · Neuron · doi:10.1016/j.neuron.2007.01.010 · Cited by 2,208 · cited 4×
“Importantly, 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).”
BackgroundInfluentialDecreased Clearance of CNS β-Amyloid in Alzheimer’s Disease
Mawuenyega, K. G., Sigurdson, W., Ovod, V., Munsell, L., Kasten, T., Morris, J. C., Yarasheski, K. E., & Bateman, R. J. (2010) · Science · doi:10.1126/science.1197623 · Cited by 2,078
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Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease
Corder, E. H., Saunders, A. M., Risch, N. J., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Rimmler, J. B., Locke, P. A., Conneally, P. M., Schmader, K. E., et al. (1994) · Nature Genetics · doi:10.1038/ng0694-180 · Cited by 1,920
Microglial physiology: unique stimuli, specialized responses
Ransohoff, R. M., & Perry, V. H. (2009) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132528 · Cited by 1,858 · cited 1×
“Relative to apoE3, apoE4 appears to reduce the clearance of Aβ and increase its deposition in plaques (Rebeck et al., 1993; Kok et al., 2009; Reiman et al., 2009; Castellano et al., 2011; Fleisher et al., 2013).”
BackgroundTREM2 Lipid Sensing Sustains the Microglial Response in an Alzheimer’s Disease Model
Wang, Y., Cella, M., Mallinson, K., Ulrich, J. D., Young, K. L., Robinette, M. L., Gilfillan, S., Krishnan, G. M., Sudhakar, S., Zinselmeyer, B. H., et al. (2015) · Cell · doi:10.1016/j.cell.2015.01.049 · Cited by 1,736 · cited 7×
“mRNA profiles of microglia sorted by flow cytometry from the brains of β-amyloid mouse models show marked changes in expression of hundreds of genes (Orre et al., 2014; Wang et al., 2015; Srinivasan et al., 2016; Keren-Shaul et al., 2017).”
BackgroundInfluentialDepletion of microglia and inhibition of exosome synthesis halt tau propagation
Asai, H., Ikezu, S., Tsunoda, S., Medalla, M., Luebke, J., Haydar, T., Wolozin, B., Butovsky, O., Kügler, S., & Ikezu, T. (2015) · Nature Neuroscience · doi:10.1038/nn.4132 · Cited by 1,591 · cited 5×
“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).”
BackgroundInfluentialUber eine eigenartige Erkrankung der Hirnrinde
Alzheimer, A. (1907) · Medical Entomology and Zoology · Cited by 1,503
Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways
Kierdorf, K., Erny, D., Goldmann, T., Sander, V., Schulz, C., Perdiguero, E. G., Wieghofer, P., Heinrich, A., Riemke, P., Hölscher, C., et al. (2013) · Nature Neuroscience · doi:10.1038/nn.3318 · Cited by 1,457 · cited 1×
“…copy number and expression of complement factor C4A (Sekar et al., 2016), and genetic variants in complement proteins and regulators (most notably CFH) that lead to increased complement activity are highly associated with age-related macular degeneration (Klein et al., 2005; Boyer et al., 2017).”
BackgroundAn english translation of alzheimer’s 1907 paper, “über eine eigenartige erkankung der hirnrinde”
Stelzmann, R. A., Norman Schnitzlein, H., & Reed Murtagh, F. (1995) · Clinical Anatomy · doi:10.1002/ca.980080612 · Cited by 1,455
TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease
Ulland, T. K., Song, W. M., Huang, S. C.-C., Ulrich, J. D., Sergushichev, A., Beatty, W. L., Loboda, A. A., Zhou, Y., Cairns, N. J., Kambal, A., et al. (2017) · Cell · doi:10.1016/j.cell.2017.07.023 · Cited by 1,263 · cited 1×
“A recent study suggested that the multifaceted microglial dysfunction observed in TREM2-deficient mice with β-amyloid pathology could stem from impaired mTOR signaling and a metabolic deficit (Ulland et al., 2017).”
BackgroundHuman ApoE isoforms differentially regulate brain amyloid-β peptide clearance
Castellano, J. M., Kim, J., Stewart, F. R., Jiang, H., DeMattos, R. B., Patterson, B. W., Fagan, A. M., Morris, J. C., Mawuenyega, K. G., Cruchaga, C., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002156 · Cited by 1,242
An environment-dependent transcriptional network specifies human microglia identity
Gosselin, D., Skola, D., Coufal, N. G., Holtman, I. R., Schlachetzki, J. C. M., Sajti, E., Jaeger, B. N., O’Connor, C., Fitzpatrick, C., Pasillas, M. P., et al. (2017) · Science · doi:10.1126/science.aal3222 · Cited by 1,220
ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy
Initiative, A. D. N., Shi, Y., Yamada, K., Liddelow, S. A., Smith, S. T., Zhao, L., Luo, W., Tsai, R. M., Spina, S., Grinberg, L. T., et al. (2017) · Nature · doi:10.1038/nature24016 · Cited by 1,220
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“In the CNS, microglia serve as resident phagocytes that dynamically survey the environment, playing crucial roles in CNS tissue maintenance, injury response, and pathogen defense (Nayak et al., 2014; Colonna and Butovsky, 2017).”
BackgroundMicroglia development and function
Nayak, D., Roth, T. L., & McGavern, D. B. (2014) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032713-120240 · Cited by 1,154 · cited 1×
“In the normal brain, microglia dynamically extend and retract processes to probe the environment (Nimmerjahn et al., 2005).”
BackgroundMicroglial brain region-dependent diversity and selective regional sensitivities to aging
Grabert, K., Michoel, T., Karavolos, M. H., Clohisey, S., Baillie, J. K., Stevens, M. P., Freeman, T. C., Summers, K. M., & McColl, B. W. (2016) · Nature Neuroscience · doi:10.1038/nn.4222 · Cited by 1,151
Takahashi, K., Rochford, C. D. P., & Neumann, H. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20041611 · Cited by 1,124 · cited 3×
“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).”
BackgroundThe Complement System: An Unexpected Role in Synaptic Pruning During Development and Disease
Stephan, A. H., Barres, B. A., & Stevens, B. (2012) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-061010-113810 · Cited by 1,113 · cited 1×
“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…”
BackgroundApolipoprotein E in sporadic Alzheimer's disease: Allelic variation and receptor interactions
William Rebeck, G., Reiter, J. S., Strickland, D. K., & Hyman, B. T. (1993) · Neuron · doi:10.1016/0896-6273(93)90070-8 · Cited by 1,107 · cited 1×
“Relative to apoE3, apoE4 appears to reduce the clearance of Aβ and increase its deposition in plaques (Rebeck et al., 1993; Kok et al., 2009; Reiman et al., 2009; Castellano et al., 2011; Fleisher et al., 2013).”
BackgroundARUK Consortium, Sims, R., GERAD/PERADES, C., van der Lee, S. J., Naj, A. C., Bellenguez, C., Badarinarayan, N., Jakobsdottir, J., Kunkle, B. W., Boland, A., et al. (2017) · Nature Genetics · doi:10.1038/ng.3916 · Cited by 1,012
Alzheimer’s Disease Risk Gene CD33 Inhibits Microglial Uptake of Amyloid Beta
Griciuc, A., Serrano-Pozo, A., Parrado, A. R., Lesinski, A. N., Asselin, C. N., Mullin, K., Hooli, B., Choi, S. H., Hyman, B. T., & Tanzi, R. E. (2013) · Neuron · doi:10.1016/j.neuron.2013.04.014 · Cited by 1,004
Yeh, F. L., Wang, Y., Tom, I., Gonzalez, L. C., & Sheng, M. (2016) · Neuron · doi:10.1016/j.neuron.2016.06.015 · Cited by 943
Self-citationOrigin and differentiation of microglia
Ginhoux, F., Lim, S., Hoeffel, G., Low, D., & Huber, T. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00045 · Cited by 905
Innate immunity in Alzheimer's disease
Heneka, M. T., Golenbock, D. T., & Latz, E. (2015) · Nature Immunology · doi:10.1038/ni.3102 · Cited by 902 · cited 1×
“…gene expression signature overlaps significantly with changes in microglial mRNA profiles observed in other neurodegeneration-related models including PS19 tau transgenic, SOD1-G93A transgenic, and aged mice (Chiu et al., 2013; Holtman et al., 2015; Friedman et al., 2017; Keren-Shaul et al., 2017).”
BackgroundMicroglial Phagocytosis of Live Neurons
Brown, G. C., & Neher, J. J. (2014) · Nature Reviews Neuroscience · doi:10.1038/nrn3710 · Cited by 853 · cited 1×
“The latter study suggested that TREM2 may enable the phagocytosis by microglia of stressed but viable neurons, a process termed phagoptosis (Brown and Neher, 2014).”
BackgroundTREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques
Wang, Y., Ulland, T. K., Ulrich, J. D., Song, W., Tzaferis, J. A., Hole, J. T., Yuan, P., Mahan, T. E., Shi, Y., Gilfillan, S., et al. (2016) · Journal of Experimental Medicine · doi:10.1084/jem.20151948 · Cited by 840 · cited 1×
“A progressive neurodegenerative disorder afflicting mainly the elderly, AD is the most common cause of dementia and a leading cause of death in the United States (James et al., 2014; Weuve et al., 2014).”
BackgroundMechanisms of Disease: astrocytes in neurodegenerative disease
Maragakis, N. J., & Rothstein, J. D. (2006) · Nature Clinical Practice Neurology · doi:10.1038/ncpneuro0355 · Cited by 836 · cited 1×
“Microgliosis and astrogliosis are common features of many neurodegenerative diseases with distinct etiologies (Maragakis and Rothstein, 2006; Ransohoff and Perry, 2009; Glass et al., 2010), but it was uncertain whether these histopathological changes reflect a beneficial, detrimental, or inconsequential activity of gl…”
BackgroundLack of apolipoprotein E dramatically reduces amyloid β-peptide deposition
Bales, K. R., Verina, T., Dodel, R. C., Du, Y., Altstiel, L., Bender, M., Hyslop, P., Johnstone, E. M., Little, S. P., Cummins, D. J., et al. (1997) · Nature Genetics · doi:10.1038/ng1197-263 · Cited by 830
Yuan, P., Condello, C., Keene, C. D., Wang, Y., Bird, T. D., Paul, S. M., Luo, W., Colonna, M., Baddeley, D., & Grutzendler, J. (2016) · Neuron · doi:10.1016/j.neuron.2016.05.003 · Cited by 817
Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid
Wisniewski, T., & Frangione, B. (1992) · Neuroscience Letters · doi:10.1016/0304-3940(92)90444-c · Cited by 802 · cited 1×
“In this section, 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).”
BackgroundTREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis
Kleinberger, G., Yamanishi, Y., Suárez-Calvet, M., Czirr, E., Lohmann, E., Cuyvers, E., Struyfs, H., Pettkus, N., Wenninger-Weinzierl, A., Mazaheri, F., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3009093 · Cited by 798 · cited 1×
“Homozygous null mutations in TREM2 cause Nasu–Hakola disease, characterized by early onset neurodegeneration (including white matter lesions) and bone abnormalities (Paloneva et al., 2002; Klünemann et al., 2005).”
BackgroundReiman, E. M., Chen, K., Liu, X., Bandy, D., Yu, M., Lee, W., Ayutyanont, N., Keppler, J., Reeder, S. A., Langbaum, J. B. S., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0900345106 · Cited by 785
Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease
Holtzman, D. M., Herz, J., & Bu, G. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006312 · Cited by 782
Transcriptomic analysis of purified human cortical microglia reveals age-associated changes
Galatro, T. F., Holtman, I. R., Lerario, A. M., Vainchtein, I. D., Brouwer, N., Sola, P. R., Veras, M. M., Pereira, T. F., Leite, R. E. P., Möller, T., et al. (2017) · Nature Neuroscience · doi:10.1038/nn.4597 · Cited by 741
Lui, H., Zhang, J., Makinson, S. R., Cahill, M. K., Kelley, K. W., Huang, H.-Y., Shang, Y., Oldham, M. C., Martens, L. H., Gao, F., et al. (2016) · Cell · doi:10.1016/j.cell.2016.04.001 · Cited by 729
Streit, W. J., Braak, H., Xue, Q.-S., & Bechmann, I. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0556-6 · Cited by 727 · cited 1×
“Relative to the most common apoE3 variant, a single apoE4 or apoE2 allele confers an approximately threefold increased or approximately twofold reduced risk of developing AD, respectively (Corder et al., 1993, 1994; Strittmatter et al., 1993; Farrer et al., 1997).”
BackgroundHyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms
Andorfer, C., Kress, Y., Espinoza, M., De Silva, R., Tucker, K. L., Barde, Y., Duff, K., & Davies, P. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.01879.x · Cited by 722
Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques
Condello, C., Yuan, P., Schain, A., & Grutzendler, J. (2015) · Nature Communications · doi:10.1038/ncomms7176 · Cited by 718 · cited 1×
“Relative to the most common apoE3 variant, a single apoE4 or apoE2 allele confers an approximately threefold increased or approximately twofold reduced risk of developing AD, respectively (Corder et al., 1993, 1994; Strittmatter et al., 1993; Farrer et al., 1997).”
BackgroundDystrophic microglia in the aging human brain
Streit, W. J., Sammons, N. W., Kuhns, A. J., & Sparks, D. L. (2004) · Glia · doi:10.1002/glia.10319 · Cited by 705
Spangenberg, E. E., Lee, R. J., Najafi, A. R., Rice, R. A., Elmore, M. R. P., Blurton-Jones, M., West, B. L., & Green, K. N. (2016) · Brain · doi:10.1093/brain/aww016 · Cited by 695 · cited 2×
“1 A; Srinivasan et al., 2016; Zhang et al., 2016).”
BackgroundCutting Edge: TREM-2 Attenuates Macrophage Activation
Turnbull, I. R., Gilfillan, S., Cella, M., Aoshi, T., Miller, M., Piccio, L., Hernandez, M., & Colonna, M. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.6.3520 · Cited by 688
Paloneva, J., Manninen, T., Christman, G., Hovanes, K., Mandelin, J., Adolfsson, R., Bianchin, M., Bird, T., Miranda, R., Salmaggi, A., et al. (2002) · The American Journal of Human Genetics · doi:10.1086/342259 · Cited by 683
Jay, T. R., Miller, C. M., Cheng, P. J., Graham, L. C., Bemiller, S., Broihier, M. L., Xu, G., Margevicius, D., Karlo, J. C., Sousa, G. L., et al. (2015) · Journal of Experimental Medicine · doi:10.1084/jem.20142322 · Cited by 682 · cited 1×
“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).”
BackgroundA complement–microglial axis drives synapse loss during virus-induced memory impairment
Vasek, M. J., Garber, C., Dorsey, D., Durrant, D. M., Bollman, B., Soung, A., Yu, J., Perez-Torres, C., Frouin, A., Wilton, D. K., et al. (2016) · Nature · doi:10.1038/nature18283 · Cited by 671
Friedman, B. A., Srinivasan, K., Ayalon, G., Meilandt, W. J., Lin, H., Huntley, M. A., Cao, Y., Lee, S.-H., Haddick, P. C. G., Ngu, H., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2017.12.066 · Cited by 662
Self-citationMicroglia: Dynamic Mediators of Synapse Development and Plasticity
Wu, Y., Dissing-Olesen, L., MacVicar, B. A., & Stevens, B. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.08.008 · Cited by 661 · cited 2×
“…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 (Wyss-Coray et al., 2002; Maier et al., 2008; Shi et al., 2017a).”
BackgroundChiu, I. M., Morimoto, E. T. A., Goodarzi, H., Liao, J. T., O’Keeffe, S., Phatnani, H. P., Muratet, M., Carroll, M. C., Levy, S., Tavazoie, S., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.06.018 · Cited by 651 · cited 1×
“Interestingly, whereas a reduction in plaque load was observed with Cx3cr1 knockout in amyloid models (Lee et al., 2010; Liu et al., 2010), this was reportedly accompanied by increased proinflammatory cytokines, tau pathology, and functional deficits (Cho et al., 2011; Lee et al., 2014).”
BackgroundRegulation of Tau Pathology by the Microglial Fractalkine Receptor
Bhaskar, K., Konerth, M., Kokiko-Cochran, O. N., Cardona, A., Ransohoff, R. M., & Lamb, B. T. (2010) · Neuron · doi:10.1016/j.neuron.2010.08.023 · Cited by 639
Holtman, I. R., Raj, D. D., Miller, J. A., Schaafsma, W., Yin, Z., Brouwer, N., Wes, P. D., Möller, T., Orre, M., Kamphuis, W., et al. (2015) · Acta Neuropathologica Communications · doi:10.1186/s40478-015-0203-5 · Cited by 619
Maphis, N., Xu, G., Kokiko-Cochran, O. N., Jiang, S., Cardona, A., Ransohoff, R. M., Lamb, B. T., & Bhaskar, K. (2015) · Brain · doi:10.1093/brain/awv081 · Cited by 595
Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice
Shi, Q., Chowdhury, S., Ma, R., Le, K. X., Hong, S., Caldarone, B. J., Stevens, B., & Lemere, C. A. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aaf6295 · Cited by 593
Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)
Atagi, Y., Liu, C.-C., Painter, M. M., Chen, X.-F., Verbeeck, C., Zheng, H., Li, X., Rademakers, R., Kang, S. S., Xu, H., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.679043 · Cited by 587 · cited 5×
“, low density lipoprotein [LDL] and HDL), and apoptotic cells (Atagi et al., 2015; Bailey et al., 2015; Poliani et al., 2015; Wang et al., 2015; Yeh et al., 2016).”
BackgroundInfluentialCD33 Alzheimer's disease locus: altered monocyte function and amyloid biology
Initiative, T. A. D. N., Bradshaw, E. M., Chibnik, L. B., Keenan, B. T., Ottoboni, L., Raj, T., Tang, A., Rosenkrantz, L. L., Imboywa, S., Lee, M., et al. (2013) · Nature Neuroscience · doi:10.1038/nn.3435 · Cited by 570
Immune proteins in brain development and synaptic plasticity
Boulanger, L. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.09.001 · Cited by 555 · cited 1×
“…copy number and expression of complement factor C4A (Sekar et al., 2016), and genetic variants in complement proteins and regulators (most notably CFH) that lead to increased complement activity are highly associated with age-related macular degeneration (Klein et al., 2005; Boyer et al., 2017).”
BackgroundEndophilin marks and controls a clathrin-independent endocytic pathway
Boucrot, E., Ferreira, A. P. A., Almeida-Souza, L., Debard, S., Vallis, Y., Howard, G., Bertot, L., Sauvonnet, N., & McMahon, H. T. (2015) · Nature · doi:10.1038/nature14067 · Cited by 542 · cited 1×
“…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).”
BackgroundOlmos-Alonso, A., Schetters, S. T. T., Sri, S., Askew, K., Mancuso, R., Vargas-Caballero, M., Holscher, C., Perry, V. H., & Gomez-Nicola, D. (2016) · Brain · doi:10.1093/brain/awv379 · Cited by 532 · cited 1×
“…understanding the role of microglia in neurodegeneration. mRNA profiles of microglia sorted by flow cytometry from the brains of β-amyloid mouse models show marked changes in expression of hundreds of genes (Orre et al., 2014; Wang et al., 2015; Srinivasan et al., 2016; Keren-Shaul et al., 2017).”
BackgroundTREM2 sustains microglial expansion during aging and response to demyelination
Poliani, P. L., Wang, Y., Fontana, E., Robinette, M. L., Yamanishi, Y., Gilfillan, S., & Colonna, M. (2015) · Journal of Clinical Investigation · doi:10.1172/jci77983 · Cited by 525 · cited 1×
“The protective SNP alters CD33 mRNA splicing such that the extracellular sialic acid–binding domain is lost from the final protein (Malik et al., 2013, 2015; Raj et al., 2014).”
BackgroundLee, S., Varvel, N. H., Konerth, M. E., Xu, G., Cardona, A. E., Ransohoff, R. M., & Lamb, B. T. (2010) · The American Journal of Pathology · doi:10.2353/ajpath.2010.100265 · Cited by 522 · cited 1×
“Interestingly, whereas a reduction in plaque load was observed with Cx3cr1 knockout in amyloid models (Lee et al., 2010; Liu et al., 2010), this was reportedly accompanied by increased proinflammatory cytokines, tau pathology, and functional deficits (Cho et al.”
BackgroundHamelin, L., Lagarde, J., Dorothée, G., Leroy, C., Labit, M., Comley, R. A., de Souza, L. C., Corne, H., Dauphinot, L., Bertoux, M., et al. (2016) · Brain · doi:10.1093/brain/aww017 · Cited by 519
Leyns, C. E. G., Ulrich, J. D., Finn, M. B., Stewart, F. R., Koscal, L. J., Remolina Serrano, J., Robinson, G. O., Anderson, E., Colonna, M., & Holtzman, D. M. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1710311114 · Cited by 517 · cited 3×
“, 2017); however, this is debatable, because TREM2 facilitates neurodegeneration in the PS19 model (Leyns et al., 2017) and is presumably required for the up-regulation of DAM genes in that model (Friedman et al.”
BackgroundInfluentialBales, K. R., Verina, T., Cummins, D. J., Du, Y., Dodel, R. C., Saura, J., Fishman, C. E., DeLong, C. A., Piccardo, P., Petegnief, V., et al. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.26.15233 · Cited by 486
A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia
Hsieh, C. L., Koike, M., Spusta, S. C., Niemi, E. C., Yenari, M., Nakamura, M. C., & Seaman, W. E. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06042.x · Cited by 475
Alzheimer’s Disease Genetics: From the Bench to the Clinic
Karch, C. M., Cruchaga, C., & Goate, A. M. (2014) · Neuron · doi:10.1016/j.neuron.2014.05.041 · Cited by 473
ApoE and Clusterin Cooperatively Suppress Aβ Levels and Deposition
DeMattos, R. B., Cirrito, J. R., Parsadanian, M., May, P. C., O'Dell, M. A., Taylor, J. W., Harmony, J. A. K., Aronow, B. J., Bales, K. R., Paul, S. M., et al. (2004) · Neuron · doi:10.1016/s0896-6273(03)00850-x · Cited by 459 · 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).”
Disease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer's Disease
Jay, T. R., Hirsch, A. M., Broihier, M. L., Miller, C. M., Neilson, L. E., Ransohoff, R. M., Lamb, B. T., & Landreth, G. E. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.2110-16.2016 · Cited by 457 · cited 2×
“Consistent with this notion, plaque accumulation in mouse models of β-amyloidosis (which typically overexpress mutant APP together with mutant PS1 or PS2) is exacerbated at later ages (8+ months) in Trem2 knockout mice (Wang et al., 2015; Jay et al., 2017a).”
BackgroundMitochondrial dysfunction remodels one-carbon metabolism in human cells
Bao, X. R., Ong, S., Goldberger, O., Peng, J., Sharma, R., Thompson, D. A., Vafai, S. B., Cox, A. G., Marutani, E., Ichinose, F., et al. (2016) · eLife · doi:10.7554/elife.10575 · Cited by 450
Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice
Wyss-Coray, T., Yan, F., Lin, A. H.-T., Lambris, J. D., Alexander, J. J., Quigg, R. J., & Masliah, E. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.162350199 · Cited by 446 · cited 8×
“Importantly, 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).”
BackgroundInfluentialHamerman, J. A., Jarjoura, J. R., Humphrey, M. B., Nakamura, M. C., Seaman, W. E., & Lanier, L. L. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.4.2051 · Cited by 440
TREM2, microglia, and neurodegenerative diseases
Yeh, F. L., Hansen, D. V., & Sheng, M. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.03.008 · Cited by 440 · cited 1×
“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…”
BackgroundSelf-citationTREM2 in Neurodegenerative Diseases
Jay, T. R., von Saucken, V. E., & Landreth, G. E. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0197-5 · Cited by 427 · cited 1×
“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…”
BackgroundA common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease
The International Genomics of Alzheimer's Project, Huang, K.-L., Initiative, T. A. D. N., Marcora, E., Pimenova, A. A., Di Narzo, A. F., Kapoor, M., Jin, S. C., Harari, O., Bertelsen, S., et al. (2017) · Nature Neuroscience · doi:10.1038/nn.4587 · Cited by 423
A Dramatic Increase of C1q Protein in the CNS during Normal Aging
Stephan, A. H., Madison, D. V., Mateos, J. M., Fraser, D. A., Lovelett, E. A., Coutellier, L., Kim, L., Tsai, H.-H., Huang, E. J., Rowitch, D. H., et al. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.1333-13.2013 · Cited by 423 · cited 2×
“…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.”
BackgroundMicroglia Mediate the Clearance of Soluble Aβ through Fluid Phase Macropinocytosis
Mandrekar, S., Jiang, Q., Lee, C. Y. D., Koenigsknecht-Talboo, J., Holtzman, D. M., & Landreth, G. E. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.5572-08.2009 · Cited by 415
TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1
Peng, Q., Malhotra, S., Torchia, J. A., Kerr, W. G., Coggeshall, K. M., & Humphrey, M. B. (2010) · Science Signaling · doi:10.1126/scisignal.2000500 · Cited by 413 · cited 1×
“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).”
BackgroundGlial contributions to neurodegeneration in tauopathies
Leyns, C. E. G., & Holtzman, D. M. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0192-x · Cited by 409 · cited 1×
“, 2015; Spangenberg and Green, 2017) and exacerbate tau pathology (Leyns and Holtzman, 2017).”
BackgroundFormation and maintenance of Alzheimer's disease β-amyloid plaques in the absence of microglia
Grathwohl, S. A., Kälin, R. E., Bolmont, T., Prokop, S., Winkelmann, G., Kaeser, S. A., Odenthal, J., Radde, R., Eldh, T., Gandy, S., et al. (2009) · Nature Neuroscience · doi:10.1038/nn.2432 · Cited by 401
Isolation of glia from Alzheimer’s mice reveals inflammation and dysfunction
Orre, M., Kamphuis, W., Osborn, L. M., Jansen, A. H. P., Kooijman, L., Bossers, K., & Hol, E. M. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.06.004 · Cited by 394 · cited 1×
“Homozygous null mutations in TREM2 cause Nasu–Hakola disease, characterized by early onset neurodegeneration (including white matter lesions) and bone abnormalities (Paloneva et al., 2002; Klünemann et al., 2005).”
BackgroundGhosh, S., Wu, M. D., Shaftel, S. S., Kyrkanides, S., LaFerla, F. M., Olschowka, J. A., & O'Banion, M. K. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.4361-12.2013 · Cited by 390
Do glia drive synaptic and cognitive impairment in disease?
Chung, W.-S., Welsh, C. A., Barres, B. A., & Stevens, B. (2015) · Nature Neuroscience · doi:10.1038/nn.4142 · Cited by 385
Microglia: Architects of the Developing Nervous System
Frost, J. L., & Schafer, D. P. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2016.02.006 · Cited by 382
Contribution of Alzheimer disease to mortality in the United States
James, B. D., Leurgans, S. E., Hebert, L. E., Scherr, P. A., Yaffe, K. S., & Bennett, D. A. (2014) · Neurology · doi:10.1212/wnl.0000000000000240 · Cited by 377
Kawabori, M., Kacimi, R., Kauppinen, T., Calosing, C., Kim, J. Y., Hsieh, C. L., Nakamura, M. C., & Yenari, M. A. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.2620-14.2015 · Cited by 375
Complement C3-Deficient Mice Fail to Display Age-Related Hippocampal Decline
Shi, Q., Colodner, K. J., Matousek, S. B., Merry, K., Hong, S., Kenison, J. E., Frost, J. L., Le, K. X., Li, S., Dodart, J.-C., et al. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.1698-15.2015 · Cited by 368
Inflammation in Alzheimer’s disease: Lessons learned from microglia-depletion models
Spangenberg, E. E., & Green, K. N. (2017) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2016.07.003 · Cited by 352 · cited 1×
“In this section, 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).”
BackgroundTREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury
Mazaheri, F., Snaidero, N., Kleinberger, G., Madore, C., Daria, A., Werner, G., Krasemann, S., Capell, A., Trümbach, D., Wurst, W., et al. (2017) · The EMBO Reports · doi:10.15252/embr.201743922 · Cited by 351 · cited 1×
“…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).”
BackgroundCombs, C. K., Johnson, D. E., Cannady, S. B., Lehman, T. M., & Landreth, G. E. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-03-00928.1999 · Cited by 349
Absence of C1q Leads to Less Neuropathology in Transgenic Mouse Models of Alzheimer's Disease
Fonseca, M. I., Zhou, J., Botto, M., & Tenner, A. J. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.0901-04.2004 · Cited by 345 · cited 1×
“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).”
BackgroundCell-specific deletion of C1qa identifies microglia as the dominant source of C1q in mouse brain
Fonseca, M. I., Chu, S.-H., Hernandez, M. X., Fang, M. J., Modarresi, L., Selvan, P., MacGregor, G. R., & Tenner, A. J. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-0814-9 · Cited by 337
Untangling the brain’s neuroinflammatory and neurodegenerative transcriptional responses
Srinivasan, K., Friedman, B. A., Larson, J. L., Lauffer, B. E., Goldstein, L. D., Appling, L. L., Borneo, J., Poon, C., Ho, T., Cai, F., et al. (2016) · Nature Communications · doi:10.1038/ncomms11295 · Cited by 336
Self-citationJiang, H., Burdick, D., Glabe, C. G., Cotman, C. W., & Tenner, A. J. (1994) · The Journal of Immunology · doi:10.4049/jimmunol.152.10.5050 · Cited by 330 · cited 1×
“Although the binding partner for C1q at synapses that leads to activation of the C1 complex during synapse pruning remains unknown, it is noteworthy that C1q binding to Aβ can trigger activation of the classical complement cascade (Jiang et al., 1994; Rosen and Stevens, 2010).”
BackgroundElucidating the Role of TREM2 in Alzheimer’s Disease
Ulrich, J. D., Ulland, T. K., Colonna, M., & Holtzman, D. M. (2017) · Neuron · doi:10.1016/j.neuron.2017.02.042 · Cited by 325 · cited 1×
“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…”
BackgroundMaier, M., Peng, Y., Jiang, L., Seabrook, T. J., Carroll, M. C., & Lemere, C. A. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.0829-08.2008 · Cited by 323 · cited 2×
“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 (Wyss-Coray et al.”
BackgroundTREM2 Promotes Microglial Survival by Activating Wnt/β-Catenin Pathway
Zheng, H., Jia, L., Liu, C.-C., Rong, Z., Zhong, L., Yang, L., Chen, X.-F., Fryer, J. D., Wang, X., Zhang, Y.-W., et al. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.2459-16.2017 · Cited by 317
The Triggering Receptor Expressed on Myeloid Cells 2 Binds Apolipoprotein E
Bailey, C. C., DeVaux, L. B., & Farzan, M. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.677286 · Cited by 303
Apolipoprotein E–dependent accumulation of Alzheimer disease–related lesions begins in middle age
Kok, E., Haikonen, S., Luoto, T., Huhtala, H., Goebeler, S., Haapasalo, H., & Karhunen, P. J. (2009) · Annals of Neurology · doi:10.1002/ana.21696 · Cited by 299
Bemiller, S. M., McCray, T. J., Allan, K., Formica, S. V., Xu, G., Wilson, G., Kokiko-Cochran, O. N., Crish, S. D., Lasagna-Reeves, C. A., Ransohoff, R. M., et al. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0216-6 · Cited by 299
Pyk2 regulates multiple signaling events crucial for macrophage morphology and migration
Okigaki, M., Davis, C., Falasca, M., Harroch, S., Felsenfeld, D. P., Sheetz, M. P., & Schlessinger, J. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1834348100 · Cited by 299 · cited 2×
“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).”
BackgroundSong, W., Hooli, B., Mullin, K., Jin, S. C., Cella, M., Ulland, T. K., Wang, Y., Tanzi, R. E., & Colonna, M. (2017) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.07.004 · Cited by 297
TREM2 regulates microglial cell activation in response to demyelination in vivo
Cantoni, C., Bollman, B., Licastro, D., Xie, M., Mikesell, R., Schmidt, R., Yuede, C. M., Galimberti, D., Olivecrona, G., Klein, R. S., et al. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1388-1 · Cited by 296
Liu, Z., Condello, C., Schain, A., Harb, R., & Grutzendler, J. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.4403-10.2010 · Cited by 275
Boyer, D. S., Schmidt-Erfurth, U. M., Campagne, M. V. L., Henry, E. C., & Brittain, C. J. (2016) · Retina · doi:10.1097/iae.0000000000001392 · Cited by 272 · cited 1×
“…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).”
BackgroundFonseca, M. I., Ager, R. R., Chu, S.-H., Yazan, O., Sanderson, S. D., LaFerla, F. M., Taylor, S. M., Woodruff, T. M., & Tenner, A. J. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0901005 · Cited by 268 · cited 1×
“, 2012) or C5aR antagonism (Fonseca et al., 2009) reduced the extent of tau pathology.”
BackgroundCho, S.-H., Sun, B., Zhou, Y., Kauppinen, T. M., Halabisky, B., Wes, P., Ransohoff, R. M., & Gan, L. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.254268 · Cited by 268 · cited 1×
“, 2010), this was reportedly accompanied by increased proinflammatory cytokines, tau pathology, and functional deficits (Cho et al., 2011; Lee et al., 2014).”
BackgroundCD33 Alzheimer’s risk-altering polymorphism, CD33 expression, and exon 2 splicing
Malik, M., Simpson, J. F., Parikh, I., Wilfred, B. R., Fardo, D. W., Nelson, P. T., & Estus, S. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.1224-13.2013 · Cited by 262
Duan, Q., McMahon, S., Anand, P., Shah, H., Thomas, S., Salunga, H. T., Huang, Y., Zhang, R., Sahadevan, A., Lemieux, M. E., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aah5084 · Cited by 262
Liu, X., Zhan, Z., Li, D., Xu, L., Ma, F., Zhang, P., Yao, H., & Cao, X. (2011) · Nature Immunology · doi:10.1038/ni.2015 · Cited by 261
The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2
Klünemann, H. H., Ridha, B. H., Magy, L., Wherrett, J. R., Hemelsoet, D. M., Keen, R. W., De Bleecker, J. L., Rossor, M. N., Marienhagen, J., Klein, H. E., et al. (2005) · Neurology · doi:10.1212/01.wnl.0000160304.00003.ca · Cited by 254
Evidence for impaired amyloid β clearance in Alzheimer's disease
Wildsmith, K. R., Holley, M., Savage, J. C., Skerrett, R., & Landreth, G. E. (2013) · Alzheimer s Research & Therapy · doi:10.1186/alzrt187 · Cited by 248 · cited 1×
“…lipoprotein particles that transport lipids, cholesterol, and other hydrophobic 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.,…”
BackgroundAlzheimer’s-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions
Szaruga, M., Munteanu, B., Lismont, S., Veugelen, S., Horré, K., Mercken, M., Saido, T. C., Ryan, N. S., De Vos, T., Savvides, S. N., et al. (2017) · Cell · doi:10.1016/j.cell.2017.07.004 · Cited by 248
Fleisher, A., Chen, K., Quiroz, Y. T., Jakimovich, L. J., Gomez, M. G., Langois, C. M., Langbaum, J. B. S., Ayutyanont, N., Roontiva, A., Thiyyagura, P., et al. (2012) · The Lancet Neurology · doi:10.1016/s1474-4422(12)70227-2 · Cited by 246
TREM-2 (triggering receptor expressed on myeloid cells 2) is a phagocytic receptor for bacteria
N’Diaye, E.-N., Branda, C., Branda, S. S., Nevarez, L., Colonna, M., Lowell, C. A., Hamerman, J. A., & Seaman, W. E. (2009) · The Journal of Cell Biology · doi:10.1083/jcb.200808080 · Cited by 243 · cited 1×
“…(HDL)–like lipoprotein particles that transport lipids, cholesterol, and other hydrophobic 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…”
BackgroundNovel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes
Chung, W.-S., Verghese, P. B., Chakraborty, C., Joung, J., Hyman, B. T., Ulrich, J. D., Holtzman, D. M., & Barres, B. A. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1609896113 · Cited by 242 · cited 1×
“Interestingly, in knock-in mice expressing human apoE variants, the apoE4 risk allele increases C1q accumulation relative to apoE2 (Chung et al., 2016).”
BackgroundImmune hyperreactivity of Aβ plaque-associated microglia in Alzheimer's disease
Yin, Z., Raj, D., Saiepour, N., Van Dam, D., Brouwer, N., Holtman, I. R., Eggen, B. J. L., Möller, T., Tamm, J. A., Abdourahman, A., et al. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.03.021 · Cited by 238
Kober, D. L., Alexander-Brett, J. M., Karch, C. M., Cruchaga, C., Colonna, M., Holtzman, M. J., & Brett, T. J. (2016) · eLife · doi:10.7554/elife.20391 · Cited by 238 · cited 1×
“Relative to apoE3, apoE4 appears to reduce the clearance of Aβ and increase its deposition in plaques (Rebeck et al., 1993; Kok et al., 2009; Reiman et al., 2009; Castellano et al., 2011; Fleisher et al., 2013).”
BackgroundSynapse elimination and learning rules co-regulated by MHC class I H2-Db
Lee, H., Brott, B. K., Kirkby, L. A., Adelson, J. D., Cheng, S., Feller, M. B., Datwani, A., & Shatz, C. J. (2014) · Nature · doi:10.1038/nature13154 · Cited by 228
Brouwers, N., Van Cauwenberghe, C., Engelborghs, S., Lambert, J.-C., Bettens, K., Le Bastard, N., Pasquier, F., Montoya, A. G., Peeters, K., Mattheijssens, M., et al. (2012) · Molecular Psychiatry · doi:10.1038/mp.2011.24 · Cited by 227
Jehle, A. W., Gardai, S. J., Li, S., Linsel‐Nitschke, P., Morimoto, K., Janssen, W. J., Vandivier, R. W., Wang, N., Greenberg, S., Dale, B. M., et al. (2006) · The Journal of Cell Biology · doi:10.1083/jcb.200601030 · Cited by 213 · cited 1×
“Although the binding partner for C1q at synapses that leads to activation of the C1 complex during synapse pruning remains unknown, it is noteworthy that C1q binding to Aβ can trigger activation of the classical complement cascade (Jiang et al., 1994; Rosen and Stevens, 2010).”
BackgroundComplement Receptor 1: Disease associations and therapeutic implications
Khera, R., & Das, N. (2008) · Molecular Immunology · doi:10.1016/j.molimm.2008.09.026 · Cited by 213 · cited 1×
“For example, a common variant in SPI1 is associated with reduced AD risk and reduced SPI1 expression (Huang et al., 2017); SPI1 encodes the PU.1 transcription factor that is essential for microglial development (Schulz et al., 2012; Kierdorf et al., 2013).”
BackgroundA somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease
Mass, E., Jacome-Galarza, C. E., Blank, T., Lazarov, T., Durham, B. H., Ozkaya, N., Pastore, A., Schwabenland, M., Chung, Y. R., Rosenblum, M. K., et al. (2017) · Nature · doi:10.1038/nature23672 · Cited by 210 · cited 1×
“Late-onset AD appears to result mainly from a mixture of genetic and environmental factors, including aging, that impair the brain’s ability to clear Aβ (Mawuenyega et al., 2010; Wildsmith et al., 2013).”
BackgroundKamphuis, W., Kooijman, L., Schetters, S., Orre, M., & Hol, E. M. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2016.07.007 · Cited by 209 · cited 1×
“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).”
BackgroundFleisher, A. S., Chen, K., Liu, X., Ayutyanont, N., Roontiva, A., Thiyyagura, P., Protas, H., Joshi, A. D., Sabbagh, M., Sadowsky, C. H., et al. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.04.017 · Cited by 202
RIN3: a novel Rab5 GEF interacting with amphiphysin II involved in the early endocytic pathway
Kajiho, H., Saito, K., Tsujita, K., Kontani, K., Araki, Y., Kurosu, H., & Katada, T. (2003) · Journal of Cell Science · doi:10.1242/jcs.00718 · Cited by 191 · cited 1×
“Functions in the early endocytic pathway (Kajiho et al., 2011).”
Terwel, D., Steffensen, K. R., Verghese, P. B., Kummer, M. P., Gustafsson, J.-Å., Holtzman, D. M., & Heneka, M. T. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.6546-10.2011 · Cited by 190
Tschopp, J. F., Chonn, A., Hertig, S., & French, L. E. (1993) · The Journal of Immunology · doi:10.4049/jimmunol.151.4.2159 · Cited by 190
Deaths in the United States among persons with Alzheimer's disease (2010–2050)
Weuve, J., Hebert, L. E., Scherr, P. A., & Evans, D. A. (2014) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.01.004 · Cited by 173 · cited 1×
“Late-onset AD appears to result mainly from a mixture of genetic and environmental factors, including aging, that impair the brain’s ability to clear Aβ (Mawuenyega et al., 2010; Wildsmith et al., 2013).”
BackgroundBien-Ly, N., Gillespie, A. K., Walker, D., Yoon, S. Y., & Huang, Y. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.0033-12.2012 · Cited by 170 · cited 1×
“SHIP1 is involved in a clathrinindependent mode of receptor endocytosis (Boucrot et al., 2015) and inhibits phagocytosis in macrophages (Cox et al., 2001; Kamen et al., 2007).”
BackgroundCaglayan, S., Takagi-Niidome, S., Liao, F., Carlo, A.-S., Schmidt, V., Burgert, T., Kitago, Y., Füchtbauer, E.-M., Füchtbauer, A., Holtzman, D. M., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3007747 · Cited by 166
Cox, D., Dale, B. M., Kashiwada, M., Helgason, C. D., & Greenberg, S. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.193.1.61 · Cited by 158
Microglia limit the expansion of β-amyloid plaques in a mouse model of Alzheimer’s disease
Zhao, R., Hu, W., Tsai, J., Li, W., & Gan, W.-B. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0188-6 · Cited by 151 · cited 1×
“However, longer periods of depletion may be necessary to observe such an effect, and a study that used time-lapse imaging to track individual plaques in vivo reported that plaque size increased ∼13% over 1 wk in microglia-depleted brains (Zhao et al., 2017).”
BackgroundRaj, T., Ryan, K. J., Replogle, J. M., Chibnik, L. B., Rosenkrantz, L., Tang, A., Rothamel, K., Stranger, B. E., Bennett, D. A., Evans, D. A., et al. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddt666 · Cited by 144 · cited 1×
“A combined analysis of neuroimaging and genetic data found an association between a polymorphism in the IL1RAP gene and increased rate of Aβ accumulation in human brains of both AD and non-AD subjects (measured by Aβ-binding positron emission tomography tracer; Ramanan et al., 2015).”
BackgroundConditional eQTL analysis reveals allelic heterogeneity of gene expression
Jansen, R., Hottenga, J.-J., Nivard, M. G., Abdellaoui, A., Laport, B., de Geus, E. J., Wright, F. A., Penninx, B. W. J. H., & Boomsma, D. I. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx043 · Cited by 141 · cited 1×
“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).”
BackgroundRamanan, V. K., Risacher, S. L., Nho, K., Kim, S., Shen, L., McDonald, B. C., Yoder, K. K., Hutchins, G. D., West, J. D., Tallman, E. F., et al. (2015) · Brain · doi:10.1093/brain/awv231 · Cited by 133
Microglial complement receptor 3 regulates brain Aβ levels through secreted proteolytic activity
Czirr, E., Castello, N. A., Mosher, K. I., Castellano, J. M., Hinkson, I. V., Lucin, K. M., Baeza-Raja, B., Ryu, J. K., Li, L., Farina, S. N., et al. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20162011 · Cited by 126 · 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).”
BackgroundFarrer, L. A. (1997) · JAMA · doi:10.1001/jama.1997.03550160069041 · Cited by 124
Complement activation in very early Alzheimer disease
Zanjani, H., Finch, C. E., Kemper, C., Atkinson, J., McKeel, D., Morris, J. C., & Price, J. L. (2005) · Alzheimer Disease & Associated Disorders · doi:10.1097/01.wad.0000165506.60370.94 · Cited by 115
SP-40,40 is an inhibitor of C5b-6-initiated haemolysis
Murphy, B. F., Saunders, J. R., O’Bryan, M. K., Kirszbaum, L., Walker, I. D., & d’Apice, A. J. F. (1989) · International Immunology · doi:10.1093/intimm/1.5.551 · Cited by 115 · cited 1×
“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).”
BackgroundMcDonald, J. F., & Nelsestuen, G. L. (1997) · Biochemistry · doi:10.1021/bi962895r · Cited by 102 · cited 1×
“…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).”
BackgroundAasheim, H., Delabie, J., & Finne, E. F. (2004) · Blood · doi:10.1182/blood-2004-08-2981 · Cited by 100
Degenerating Synaptic Boutons in Prion Disease
Šišková, Z., Page, A. M., O'Connor, V. M., & Perry, V. H. (2009) · American Journal Of Pathology · doi:10.2353/ajpath.2009.090372 · Cited by 100
ABCA7 Mediates Phagocytic Clearance of Amyloid-β in the Brain
Fu, Y., Hsiao, J.-H. T., Paxinos, G., Halliday, G. M., & Kim, W. S. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160456 · Cited by 99
Fonseca, M. I., Chu, S., Pierce, A. L., Brubaker, W. D., Hauhart, R. E., Mastroeni, D., Clarke, E. V., Rogers, J., Atkinson, J. P., & Tenner, A. J. (2016) · PLOS ONE · doi:10.1371/journal.pone.0149792 · Cited by 87
Genetics of CD33 in Alzheimer's disease and acute myeloid leukemia
Malik, M., Chiles, J. W., Xi, H. S., Medway, C., Simpson, J. F., Potluri, S., Howard, D. S., Yu, L., Paumi, C. M., Mukherjee, S., et al. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv092 · Cited by 84
Lynch, J. M., Guo, L., Gélébart, P., Chilibeck, K. A., Xu, J., Molkentin, J. D., Agellon, L. B., & Michalak, M. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200412156 · Cited by 81 · cited 1×
“…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 (Wyss-Coray et al., 2002; Maier et al., 2008; Shi et al., 2017a).”
BackgroundDifferential Association of Phosphatidylinositol 3-Kinase, SHIP-1, and PTEN with Forming Phagosomes
Kamen, L. A., Levinsohn, J. L., & Swanson, J. A. (2007) · Molecular Biology of the Cell · doi:10.1091/mbc.e07-01-0061 · Cited by 79 · cited 1×
“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).”
BackgroundZhan, S., Veerhuis, R., Kamphorst, W., & Eikelenboom, P. (1995) · Neurodegeneration · doi:10.1016/1055-8330(95)90018-7 · Cited by 72
The Role of the Classical Complement Cascade in Synapse Loss During Development and Glaucoma
Rosen, A. M., & Stevens, B. (2010) · Advances in Experimental Medicine and Biology · doi:10.1007/978-1-4419-5635-4_6 · Cited by 60 · cited 1×
“CD2AP Adaptor protein between membrane proteins and actin cytoskeleton Interactions with SHIP1 and RIN3 (Bao et al., 2012; Rouka et al., 2015) suggest role in microglia endocytosis.”
BackgroundCharacterization of RIN3 as a Guanine Nucleotide Exchange Factor for the Rab5 Subfamily GTPase Rab31
Kajiho, H., Sakurai, K., Minoda, T., Yoshikawa, M., Nakagawa, S., Fukushima, S., Kontani, K., & Katada, T. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.172445 · Cited by 59
Bao, M., Hanabuchi, S., Facchinetti, V., Du, Q., Bover, L., Plumas, J., Chaperot, L., Cao, W., Qin, J., Sun, S.-C., et al. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1200887 · Cited by 49 · cited 1×
“Occurring during the decade or two preceding dementia symptoms (Bateman et al., 2012; Fleisher et al., 2012; Villemagne et al., 2013), β-amyloidosis results from an imbalance in the production versus clearance of Aβ.”
BackgroundRouka, E., Simister, P. C., Janning, M., Kumbrink, J., Konstantinou, T., Muniz, J. R. C., Joshi, D., O’Reilly, N., Volkmer, R., Ritter, B., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.637207 · Cited by 47
An unprecedented march for science
Appenzeller, T., & Staff, S. N. (2017) · Science · doi:10.1126/science.356.6336.356 · Cited by 46
Britschgi, M., Takeda-Uchimura, Y., Rockenstein, E., Johns, H., Masliah, E., & Wyss-Coray, T. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-220 · Cited by 45 · cited 1×
“Variant with extra C3b/ C4b-binding domain increases AD risk (Brouwers et al., 2012).”
BackgroundThe NESH/Abi-3-based WAVE2 complex is functionally distinct from the Abi-1-based WAVE2 complex
Sekino, S., Kashiwagi, Y., Kanazawa, H., Takada, K., Baba, T., Sato, S., Inoue, H., Kojima, M., & Tani, K. (2015) · Cell Communication and Signaling · doi:10.1186/s12964-015-0119-5 · Cited by 43
The Role of Complement Dysregulation in AMD Mouse Models
Ding, J., Kelly, U., Groelle, M., Christenbury, J. G., Zhang, W., & Rickman, C. B. (2014) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-3209-8_28 · Cited by 22 · 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).”
BackgroundThe Role of Activity in Synaptic Degeneration in a Protein Misfolding Disease, Prion Disease
Caleo, M., Restani, L., Vannini, E., Šišková, Z., Al-Malki, H., Morgan, R. S. M., O'Connor, V. M., & Perry, V. H. (2012) · PLoS ONE · doi:10.1371/journal.pone.0041182 · Cited by 21
Flagged first, then by citations
Research works printed but not linked: 1
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Cited by
Sorted by citations
Scheltens, P., De Strooper, B., Kivipelto, M., Holstege, H., Chételat, G., Teunissen, C. E., Cummings, J., & van der Flier, W. M. (2021) · The Lancet · doi:10.1016/s0140-6736(20)32205-4 · Cited by 5,465
Inflammation in obesity, diabetes, and related disorders
Rohm, T. V., Meier, D. T., Olefsky, J. M., & Donath, M. Y. (2022) · Immunity · doi:10.1016/j.immuni.2021.12.013 · Cited by 2,066
Role of neuroinflammation in neurodegeneration development
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“In normal human brains, APOE is mainly derived from astrocytes,(35,163) while its expression by microglia is induced by ageing as well as amyloid and tau pathology.(35,164,165) There are three isoforms of APOE gene in humans, respectively, APOE2, APOE3, APOE4.”
BackgroundSpatial Transcriptomics and In Situ Sequencing to Study Alzheimer’s Disease
Chen, W.-T., Lu, A., Craessaerts, K., Pavie, B., Sala Frigerio, C., Corthout, N., Qian, X., Laláková, J., Kühnemund, M., Voytyuk, I., et al. (2020) · Cell · doi:10.1016/j.cell.2020.06.038 · Cited by 949
Microglia polarization from M1 to M2 in neurodegenerative diseases
Guo, S., Wang, H., & Yin, Y. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.815347 · Cited by 920
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
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.
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