Microglia in Alzheimer’s disease
Open accessAbstract
Proliferation and activation of microglia in the brain, concentrated around amyloid plaques, is a prominent feature of Alzheimer’s disease (AD). Human genetics data point to a key role for microglia in the pathogenesis of AD. The majority of risk genes for AD are highly expressed (and many are selectively expressed) by microglia in the brain. There is mounting evidence that microglia protect against the incidence of AD, as impaired microglial activities and altered microglial responses to β-amyloid are associated with increased AD risk. On the other hand, there is also abundant evidence that activated microglia can be harmful to neurons. Microglia can mediate synapse loss by engulfment of synapses, likely via a complement-dependent mechanism; they can also exacerbate tau pathology and secrete inflammatory factors that can injure neurons directly or via activation of neurotoxic astrocytes. Gene expression profiles indicate multiple states of microglial activation in neurodegenerative disease settings, which might explain the disparate roles of microglia in the development and progression of AD pathology.
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TL;DR
This review synthesizes human genetic and cell-biological evidence that microglia play a dual role in Alzheimer's disease: protective early (TREM2-dependent clearance and compaction of Aβ) and harmful later (complement-mediated synapse engulfment, inflammatory cytokine release, and tau pathology spread). The authors propose that the detrimental microglial state emerges later in disease, complicating therapeutic strategies that target microglia.
Key findings
- Human genetics implicate microglia in late-onset AD: over 20 loci associate with AD risk, and most identified risk genes are expressed selectively or preferentially in microglia; apart from APOE, common variants confer only minor effects (∼10–20%) on AD risk.
- The TREM2 R47H variant (carried by <0.5% of most populations) increases AD risk approximately threefold and appears to be a loss-of-function mutation impairing TREM2-mediated microglial activation, ligand binding (apoE, apoJ/CLU), and Aβ uptake; Trem2 knockout exacerbates plaque accumulation at later ages (8+ months) in β-amyloidosis mouse models.
- APOE genotype strongly modulates risk: relative to apoE3, a single apoE4 allele confers approximately threefold increased risk and apoE2 approximately twofold reduced risk; apoE4 appears to reduce Aβ clearance and increase plaque deposition.
- Microglia can be harmful: complement (C1q, C3) and microglia mediate synapse loss in amyloid models, CSF1R-inhibitor microglia depletion protects against synapse loss and rescues behavioral deficits, and microglia are implicated in tau spread; in microglia-depleted brains plaque size increased ∼13% over 1 wk.
- Transcriptional profiling identifies a disease-associated microglial (DAM) state with reduced homeostatic genes (e.g., Cx3cr1, P2ry12, Tmem119) and induced neurodegeneration genes (e.g., Apoe, Axl, Csf1, Clec7a, Cst7, Igf1, Itgax), with subtle two- to threefold increases in Trem2 and Tyrobp mRNAs; DAM induction depends largely on TREM2.
Methods
- Narrative review (Hansen, Hanson, and Sheng) synthesizing human genetics (GWAS and rare-variant studies), mouse model studies, and microglial transcriptomic profiling; no primary data are generated.
- Evidence reviewed includes GWAS-identified AD risk loci (Table 1), TREM2 and other microglial risk genes, complement-pathway and microglia-depletion experiments in amyloid and tau mouse models (Fig. 3), and RNA-sequencing/single-cell studies of microglial activation states.
- The authors integrate these findings into a proposed two-phase model of microglial function in AD pathogenesis.
Limitations
- Stated by the paper: exactly how microglia are involved in the disease mechanism "is not settled"; evidence for microglial-mediated neuronal damage comes "mostly in mouse models"; TREM2 studies in tau models report seemingly conflicting roles (neuroprotective in PS19 vs. neurotoxic in hTau) that the authors attribute partly to analysis at different disease stages; whether the TREM2-dependent transcriptional response is helpful, damaging, or incidental in different disease contexts requires further study.
- Stated by the paper: studies of microglial gene expression in purified microglia or at the single-cell level from AD brains "have lagged behind" mouse work, and there was "surprisingly limited overlap" in aging-regulated microglial genes between human and mouse, underscoring the need for human microglia profiling at different disease stages and genotypes.
- Evident from the text: many mechanistic conclusions rest on mouse models that overexpress mutant APP/PS1 or tau transgenes, and the authors note conflicting complement-pathway results (e.g., C3 knockout/inhibition reported both to provide neuroprotection and to increase amyloid burden), so causal direction in humans remains uncertain.
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Claims the paper makes
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- Findingcitation
The majority of Alzheimer's disease-associated risk genes are expressed selectively or preferentially in microglia relative to other brain cell types.
“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).”
Quote in the paperSubstantial claim0 of 2 sources checked - Findingcitation
In a meta-analysis of microglial transcriptomic profiles from various models of CNS diseases, we identified several modules of coordinately regulated genes, including a neurodegeneration-associated module highly similar to the DAM genes.
“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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Friedman et al., 2017
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- Premisecitation
Rare genetic variants associated with Alzheimer's disease have implicated microglia in determining the risk of Alzheimer's disease.
“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).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning
Microglial dysfunction is a contributing factor, rather than an attendant feature, of Alzheimer's disease pathogenesis.
“This broad trend implicates microglial dysfunction as a contributing factor, rather than an attendant feature, of AD pathogenesis.”
Quote in the paperSubstantial claim - Premisecitation
Aβ aggregates are much more efficiently taken up by microglia when Aβ is complexed with lipoproteins such as LDL, apoE, and CLU/apoJ.
“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).”
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- Premisecitation
The TREM2 R47H mutation increases the risk of Alzheimer's disease approximately threefold.
“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).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning
Microglia play an important role in the pathogenesis of Alzheimer's disease.
“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.”
Quote in the paperSubstantial claim - Premisecitation
During normal brain development, microglia engulf synapses and sculpt synaptic connections via a role for complement.
“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).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationcitation
Microglial engulfment of synapses likely varies with different developmental stages, brain regions, and disease states.
“Microglial engulfment of synapses likely varies with different developmental stages, brain regions, and disease states.”
Quote in the paperNot a substantial claim - Premisenone given
SHIP1 dephosphorylates phosphatidylinositol (3,4,5)-trisphosphate to phosphatidylinositol (3,4)-bisphosphate at the plasma membrane, altering the outcomes of PI3K activation.
“SHIP1 dephosphorylates phosphatidylinositol (3,4,5)-trisphosphate to phosphatidylinositol (3,4)-bisphosphate at the plasma membrane, altering the outcomes of PI3K activation.”
Quote in the paperSubstantial claim - Premisenone given
TREM2 signaling involves recruitment of tyrosine kinase SYK to the phosphorylated ITAM of DAP12 and thereby activates downstream effectors such as PI3K and Ca2+ signaling.
“TREM2 signaling involves recruitment of tyrosine kinase SYK to the phosphorylated ITAM (immunoreceptor tyrosine-based activation motif) of DAP12 and thereby activates downstream effectors such as phosphoinositide 3-kinase (PI3K) and Ca2+ signaling (Fig. 1 B).”
Quote in the paperNot a substantial claim - Premisecitation
The protective CD33 SNP alters CD33 mRNA splicing such that the extracellular sialic acid-binding domain is lost from the final protein.
“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).”
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- Premisecitation
Activated microglia can secrete toxic factors to directly or indirectly injure neurons.
“Moreover, activated microglia can secrete toxic factors to directly or indirectly injure neurons (Colonna and Butovsky, 2017; Liddelow et al., 2017).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning
Many Alzheimer's disease risk genes besides TREM2 are preferentially or selectively expressed in microglia and therefore could impinge on the same microglial activities and pathways regulated by TREM2.
“Many AD risk genes besides TREM2 are preferentially or selectively expressed in microglia (e.g., CD33, INPP5D, MS4A6A, and PLCG2) and therefore could impinge on the same microglial activities and pathways regulated by TREM2.”
Quote in the paperSubstantial claim - Premisecitation
Blood monocyte-derived macrophages from human carriers of the TREM2 R62H variant show reduced uptake of Aβ-lipoprotein complexes.
“Blood monocyte–derived macrophages from human carriers of the TREM2 AD-linked R62H variant showed reduced uptake of Aβ–lipoprotein complexes (Yeh et al., 2016).”
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- Premisecitation
The Alzheimer's disease-associated INPP5D SNP rs35349669 increases INPP5D gene expression in whole blood.
“The AD-associated INPP5D SNP (rs35349669) increases INPP5D gene expression in whole blood (Jansen et al., 2017).”
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- Interpretationreasoning
Compaction of protofibrillary Aβ into a dense core plaque could be a protective mechanism that limits neurotoxicity of amyloid deposits once they start to build up in the aging brain.
“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.”
Quote in the paperSubstantial claim- Rests on an assumption: Soluble oligomeric Aβ is the form that exerts the most toxic effects on neurons.
- Premisecitation
Plaque accumulation in mouse models of β-amyloidosis is exacerbated at later ages (8+ months) in Trem2 knockout mice.
“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).”
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- cites Jay et al., 2017a
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- Premisecitation
Higher TSPO signal in the brains of slow decliners is consistent with a protective role for microglial activation even in stages of Alzheimer's disease when dementia is evident.
“Another study that divided AD subjects into fast decliners and slow decliners measured a higher TSPO signal in the brains of slow decliners, consistent with a protective role for microglial activation even in stages of AD when dementia is evident (Hamelin et al., 2016).”
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- Premisecitation
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.
“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).”
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- Interpretationreasoning
Impaired uptake and clearance of Aβ could explain, at least in part, how TREM2 loss-of-function mutations increase the risk of developing Alzheimer's disease.
“Thus, impaired uptake and clearance of Aβ (perhaps as Aβ–lipoprotein complexes) could explain, at least in part, how TREM2 loss-of-function mutations increase the risk of developing AD (Fig. 2).”
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Another important TREM2-dependent function of microglia is to clean up debris from damaged or dying cells to promote a healthy brain environment, as observed in models of demyelination or ischemic stroke.
“another important TREM2-dependent function of microglia is to clean up debris from damaged or dying cells to promote a healthy brain environment, as observed in models of demyelination or ischemic stroke (Cantoni et al., 2015; Kawabori et al., 2015; Poliani et al., 2015).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning
C3 activation may be involved in clearance of plaque via classical pathway-independent mechanisms.
“Thus, in addition to mediating neuronal damage, C3 activation may be involved in clearance of plaque via classical pathway-independent mechanisms.”
Quote in the paperSubstantial claim - Premisecitation
C1q binding to Aβ can trigger activation of the classical complement cascade.
“it is noteworthy that C1q binding to Aβ can trigger activation of the classical complement cascade (Jiang et al., 1994; Rosen and Stevens, 2010).”
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- cites Rosen and Stevens, 2010
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The exacerbation of tau pathology in Cx3cr1 knockout mice was blocked with IL-1 antagonists.
“the exacerbation of tau pathology in Cx3cr1 knockout mice was blocked with IL-1 antagonists (Bhaskar et al., 2010; Maphis et al., 2015)”
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Microglia are implicated in the cell-to-cell spread of tau pathology across the brain in a mouse model of tauopathy initiated via viral expression of mutant tau.
“Studies in a mouse model of tauopathy initiated via viral expression of mutant tau have implicated microglia in the cell-to-cell spread of tau pathology across the brain, possibly mediated by microglial uptake and exosomal release of tau (Asai et al., 2015).”
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- Premisecitation
A reduction in plaque load was observed with Cx3cr1 knockout in amyloid models.
“whereas a reduction in plaque load was observed with Cx3cr1 knockout in amyloid models (Lee et al., 2010; Liu et al., 2010)”
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Microglia phagocytose synapses via CR3 during development.
“they phagocytose synapses via CR3 during development (Schafer et al., 2012)”
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- Premisecitation
Knockout of CD59 worsened pathology in a tau mouse model.
“Knockout of CD59, a protein that inhibits C5b-9 membrane attack complex formation, worsened pathology in a tau mouse model (Britschgi et al., 2012).”
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- Interpretationcitation
Microglia are likely key players in complement-mediated synapse loss in AD.
“Microglia are likely key players in complement-mediated synapse loss in AD: they are the main source of C1q in the brain (Fonseca et al., 2017), they phagocytose synapses via CR3 during development (Schafer et al., 2012), and they express the C3a and C5a receptors that trigger inflammation in response to complement activation.”
Quote in the paperSubstantial claim- Rests on an assumption: Microglia express the C3a and C5a receptors that trigger inflammation in response to complement activation.
- Premisecitation
In knock-in mice expressing human apoE variants, the apoE4 risk allele increases C1q accumulation relative to apoE2.
“in knock-in mice expressing human apoE variants, the apoE4 risk allele increases C1q accumulation relative to apoE2 (Chung et al., 2016).”
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Harmful effects of apoE4 in the context of tau pathology were associated with increased TNFα production by microglia in vitro.
“harmful effects of apoE4 in the context of tau pathology were associated with increased TNFα production by microglia in vitro (Shi et al., 2017b).”
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- Premisecitation
C3 knockout or inhibition appears to increase amyloid burden.
“though it appears to increase amyloid burden (Wyss-Coray et al., 2002; Maier et al., 2008; Shi et al., 2017a).”
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The formation and maintenance of β-amyloid plaques in amyloidosis models does not seem to be affected by CSF1R inhibition or other methods of microglia depletion.
“Unlike with synapse loss, the formation and maintenance of β-amyloid plaques in amyloidosis models does not seem to be affected by CSF1R inhibition or other methods of microglia depletion (Grathwohl et al., 2009; Olmos-Alonso et al., 2016; Spangenberg et al., 2016).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Microglia are the main source of C1q in the brain.
“they are the main source of C1q in the brain (Fonseca et al., 2017)”
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- Premisecitation
TREM2 signaling curbs TLR signaling in macrophages.
“TREM2 signaling, which is protective against AD based on human genetics, curbs TLR signaling in macrophages (Hamerman et al., 2006; Turnbull et al., 2006).”
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Genetic deletion of NLRP3, caspase-1 and TLRs have been reported to ameliorate Aβ deposition and cognitive deficits in amyloidosis mouse models.
“Genetic deletion of NLRP3, caspase-1 and TLRs have been reported to ameliorate Aβ deposition and cognitive deficits in amyloidosis mouse models, supporting the idea that “classical” inflammation exacerbates AD pathogenesis (Heneka et al., 2015).”
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- Premisecitation
In PS19 mice expressing human tau P301S and lacking murine Apoe, human apoE4 expression exacerbated tau pathology and heightened the microglial response compared with PS19 mice expressing apoE2, apoE3, or no apoE.
“a recent study in PS19 mice expressing the human tau P301S mutant transgene (Yoshiyama et al., 2007) and lacking murine Apoe showed that human apoE4 expression exacerbated tau pathology and heightened the microglial response compared with PS19 mice expressing apoE2, apoE3, or no apoE (Shi et al., 2017b).”
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- Interpretationreasoning
Human genetics point to excessive activation of the complement system as a cause of degeneration of neural tissue.
“Thus, human genetics point to excessive activation of the complement system as a cause of degeneration of neural tissue.”
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C5aR antagonism reduced the extent of tau pathology.
“C3 inhibition by transgenic expression of a soluble form of the mouse complement inhibitory protein Crry (Britschgi et al., 2012) or C5aR antagonism (Fonseca et al., 2009) reduced the extent of tau pathology.”
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- Premisecitation
Plaque size increased ∼13% over 1 wk in microglia-depleted brains.
“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).”
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- Interpretationcitation
Complement activation appears to exacerbate tau pathology in AD mouse models.
“Complement activation appears to exacerbate tau pathology in AD mouse models, though the mechanisms are unclear (Fig. 3 C).”
Quote in the paperSubstantial claim - Premisecitation
In human AD brain tissue, there is immunohistochemical evidence for activation of complement, especially associated with plaques (C1q, C3, and C4) and to a lesser extent with neurofibrillary tangles and dystrophic neurites (C5b-C9).
“In human AD brain tissue, there is considerable immunohistochemical evidence for activation of complement, especially associated with plaques (C1q, C3, and C4) and to a lesser extent with neurofibrillary tangles and dystrophic neurites (C5b-C9; Zanjani et al., 2005).”
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- Interpretationcitation
C1q appears to act downstream of Aβ.
“Notably, C1q knockout, which affects the classical pathway of complement initiation, does not impact amyloid burden, so C1q appears to act downstream of Aβ (Fonseca et al., 2004, 2017).”
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- Premisecitation
Deleting the microglial protein Cx3cr1 in transgenic tau models genetically enhanced microglial activation and accelerated the onset and progression of tau pathology.
“Deleting the microglial protein Cx3cr1 in transgenic tau models showed that genetically enhanced microglial activation accelerated the onset and progression of tau pathology (Bhaskar et al., 2010; Maphis et al., 2015).”
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Knockout or inhibition of C3 is reported to provide neuroprotection.
“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”
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- Interpretationcitation
TREM2 may enable the phagocytosis by microglia of stressed but viable neurons (phagoptosis).
“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).”
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- Premisecitation
C3 inhibition by transgenic expression of a soluble form of the mouse complement inhibitory protein Crry reduced the extent of tau pathology.
“C3 inhibition by transgenic expression of a soluble form of the mouse complement inhibitory protein Crry (Britschgi et al., 2012) or C5aR antagonism (Fonseca et al., 2009) reduced the extent of tau pathology.”
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- Premisecitation
C1q knockout does not impact amyloid burden.
“Notably, C1q knockout, which affects the classical pathway of complement initiation, does not impact amyloid burden, so C1q appears to act downstream of Aβ (Fonseca et al., 2004, 2017).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Fonseca et al., 2004, 2017
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- Premisecitation
Microglial proliferation and activation induced by a BRAF mutation restricted to erythromyeloid progenitors could drive late-onset neurodegeneration.
“a recent study using transgenic mice showed that microglial proliferation and activation induced by a BRAF mutation restricted to erythromyeloid progenitors could drive late-onset neurodegeneration (Mass et al., 2017).”
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- Premisecitation
TREM2 is presumably required for the up-regulation of DAM genes in the PS19 model.
“and is presumably required for the up-regulation of DAM genes in that model (Friedman et al., 2017).”
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- Interpretationcitation
TREM2 is required for a full inflammatory response by microglia to β-amyloid.
“which is more in keeping with the idea that TREM2 is required for a full inflammatory response by microglia to β-amyloid.”
Quote in the paperSubstantial claim - Interpretationreasoning
There is considerable evidence that microglia are responsible for neuronal damage in AD (albeit mostly in mouse models).
“Conversely, there is also considerable evidence that microglia are responsible for neuronal damage in AD (albeit mostly in mouse models).”
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TREM2 facilitates neurodegeneration in the PS19 model.
“TREM2 facilitates neurodegeneration in the PS19 model (Leyns et al., 2017)”
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- Interpretationreasoning
Transcriptional profiling of microglial gene expression suggests that different states of microglial activation may occur during the course of AD.
“Transcriptional profiling of microglial gene expression suggests that different states of microglial activation may occur during the course of AD, but more precise characterization—temporal, anatomical, and functional—is needed.”
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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.
“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).”
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Microglia from BRAF mutant mice and from brain tissue of patients with BRAF mutation-associated neurodegenerative disease showed increased inflammatory cytokine expression.
“microglia from the mutant mice as well as from brain tissue of patients with BRAF mutation–associated neurodegenerative disease showed increased inflammatory cytokine expression (Mass et al., 2017).”
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- Premisecitation
The induction of Tnf and Il1b in the brains of amyloidosis mice is dampened in TREM2-deficient mice.
“the induction of Tnf and Il1b in the brains of amyloidosis mice is dampened in TREM2-deficient mice (Wang et al., 2015; Jay et al., 2017a)”
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- cites Jay et al., 2017a
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- Premisecitation
Analyzing activated microglia as a separate population or by single-cell RNA-sequencing reveals subtle (two- to threefold) increases in Trem2 and Tyrobp mRNAs.
“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).”
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A1 astrocytes show strongly induced expression of complement proteins C1r, C1s, C3, and C4.
“Notably, A1 astrocytes show strongly induced expression of complement proteins C1r, C1s, C3, and C4 (Zamanian et al., 2012).”
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- Premisenone given
Informatics analysis of DAM genes highlights lysosomal, phagocytosis, lipid metabolism, and immune response pathways.
“Informatics analysis of DAM genes highlights lysosomal, phagocytosis, lipid metabolism, and immune response pathways.”
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TREM2-deficient microglial cells in plaque-ridden brains displayed an intermediate state of activation between "homeostatic" microglia and fully activated DAM cells.
“This method showed that that TREM2-deficient microglial cells in plaque-ridden brains displayed an intermediate state of activation between “homeostatic” microglia and fully activated DAM cells (Keren-Shaul et al., 2017).”
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- Premisecitation
The DAM 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.
“The DAM 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).”
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A1 astrocytes are found in tau transgenic mice expressing human apoE4.
“A1 astrocytes are found in tau transgenic mice expressing human apoE4 (Shi et al., 2017b)”
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- Interpretationreasoning
Astrocytes could cooperate with microglia to mediate complement-dependent neurotoxicity.
“Thus, astrocytes could cooperate with microglia to mediate complement-dependent neurotoxicity.”
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The induction of neurodegeneration-associated genes found in AD mouse models has been observed in bulk human AD brain tissue, albeit more subtle in nature.
“Nonetheless, the induction of neurodegeneration-associated genes found in AD mouse models has been observed in bulk human AD brain tissue, albeit more subtle in nature (Friedman et al., 2017).”
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- Interpretationnone given
Microglia may engulf and remove synapses via a complement-dependent mechanism.
“In particular, microglia may engulf and remove synapses via a complement-dependent mechanism, and the induction of a microglial proinflammatory state may correlate with severity of neurodegeneration.”
Quote in the paperSubstantial claim - Premisecitation
In β-amyloid models, the induction of DAM genes depends in large part on TREM2.
“In β-amyloid models, the induction of DAM genes depends in large part on TREM2, arguing that the DAM profile reflects a protective state of microglia (Wang et al., 2015; Keren-Shaul et al., 2017)”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning
The preponderance of human genetics evidence, exemplified by the large effect of loss-of-function TREM2 mutations on AD risk and on microglial function, argues that microglia have a protective function that lowers the incidence of AD.
“The preponderance of human genetics evidence, exemplified by the large effect of loss-of-function TREM2 mutations on AD risk and on microglial function, argues that microglia have a protective function that lowers the incidence of AD.”
Quote in the paperSubstantial claim - Premisecitation
Microglia proliferation preceded neuron loss in the BRAF mutant mice.
“Importantly, microglia proliferation preceded neuron loss, and microglia from the mutant mice as well as from brain tissue of patients with BRAF mutation–associated neurodegenerative disease showed increased inflammatory cytokine expression (Mass et al., 2017).”
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- Premisecitation
There was surprisingly limited overlap in microglial genes regulated by aging in human versus mouse.
“There was surprisingly limited overlap, however, in microglial genes regulated by aging in human versus mouse (Grabert et al., 2016; Galatro et al., 2017)”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationcitation
Microglia in human AD could have more severe inflammatory activation than in AD mouse models.
“suggesting that microglia in human AD could have more severe inflammatory activation than in AD mouse models.”
Quote in the paperSubstantial claim - Interpretationnone given
The induction of a microglial proinflammatory state may correlate with severity of neurodegeneration.
“and the induction of a microglial proinflammatory state may correlate with severity of neurodegeneration.”
Quote in the paperSubstantial claim - Premisecitation
An LPS-specific gene cluster, which was not induced in mouse models of neurodegeneration, showed higher expression in AD brains than in control brains.
“More interestingly, an LPS-specific gene cluster, which was not induced in mouse models of neurodegeneration, showed higher expression in AD brains than in control brains (Friedman et al., 2017)”
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- Premisecitation
A triad of factors released by activated microglia (IL-1α, TNFα, and C1q) is necessary and sufficient to induce astrocytes into a neurotoxic state termed "A1" that causes neuronal death.
“A triad of factors released by activated microglia (IL-1α, TNFα, and C1q) is necessary and sufficient to induce astrocytes into a neurotoxic state termed “A1” that causes neuronal death (Liddelow et al., 2017).”
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A1 astrocytes are reportedly found in CNS tissue from patients with various neurodegenerative diseases, including AD.
“and are reportedly found in CNS tissue from patients with various neurodegenerative diseases, including AD (Liddelow et al., 2017).”
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FindingcitationUsing 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.
“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).”
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Interpretationnone givenOnce activated, microglia can have harmful actions in Alzheimer's disease, such as being a source of inflammatory factors and mediating the engulfment of neuronal synapses.
“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.”
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Interpretationnone givenMicroglia have protective functions that restrain the toxic accumulation of β-amyloid and prevent the development of Alzheimer's disease.
“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.”
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PremisecitationTREM2-ligand interactions are impaired by TREM2 variants that increase Alzheimer's disease risk, implying that these variants are at least partial loss-of-function mutants.
“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.”
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PremisecitationTREM2 functions as a cell surface receptor on microglia; via DAP12/TYROBP, TREM2 stimulation initiates signaling that promotes microglial chemotaxis, phagocytosis, survival, and proliferation.
“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”
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PremisecitationTREM2 is required for microglial phagocytosis of apoptotic neurons, bacteria, LDL and other lipoproteins, and Aβ.
“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).”
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PremisecitationThe interaction of TREM2 with its lipoprotein ligands is impaired by the Alzheimer's disease-linked mutations R47H, R62H, and D87N and completely abolished by Nasu-Hakola disease-linked mutations Y38C and T66M.
“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).”
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- cites Bailey et al., 2015
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Premisenone givenTREM2 R47H appears to be a loss-of-function mutation that impairs TREM2-mediated microglial activation.
“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).”
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PremisecitationTREM2-deficient microglia show reduced uptake of Aβ-lipoprotein complexes in vitro and less evidence of Aβ internalization in vivo.
“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).”
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PremisecitationTREM2 binds apolipoproteins apoE and clusterin/apoJ, which are themselves encoded by Alzheimer's disease risk genes.
“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).”
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- cites Bailey et al., 2015
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PremisecitationSHIP1 can interact with the phosphorylated ITAM of DAP12, so it may moderate TREM2 signaling by competing with SYK and PI3K for ITAM occupancy.
“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).”
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InterpretationreasoningThe TREM2-apoE axis plays a key role in microglial clearance of extracellular and cellular detritus and may be generally important for minimizing bystander damage to neurons in neurodegenerative settings.
“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.”
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InterpretationcitationThe CD33 genotype-phenotype relationship aligns with TREM2: TREM2 R47H reduces TREM2-ligand binding and ITAM signaling and impairs phagocytosis, whereas the CD33 variant prevents CD33-ligand interaction and presumably ITIM signaling and promotes phagocytosis.
“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).”
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PremisecitationCompaction of protofibrillary Aβ into a dense core plaque requires apoE and is promoted by TREM2.
“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.”
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InterpretationcitationMicroglia can directly mediate synapse loss and exacerbate tau pathology.
“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).”
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- cites Spangenberg and Green, 2017
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- cites Leyns and Holtzman, 2017
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PremisecitationCarriers of the IL1RAP polymorphism showed reduced signal for microglial activation using a TSPO-binding PET tracer, increased rate of temporal lobe atrophy, and higher likelihood of progression from mild cognitive impairment to Alzheimer's disease.
“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.”
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InterpretationreasoningCollectively, TREM2 studies suggest several mechanisms by which microglia can protect from accumulation of toxic Aβ species and development of Alzheimer's disease: 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.
“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).”
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PremisecitationTREM2-deficient microglia fail to congregate or proliferate around plaques, lack the typical morphological changes of microglial activation, and show increased apoptosis.
“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).”
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PremisecitationElectron microscopy studies have detected engulfed synaptic material in the developing hippocampus but not in the hippocampus of adult mice undergoing synapse loss caused by prion disease.
“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).”
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- cites Sisková et al., 2009
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- cites Caleo et al., 2012
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PremisecitationSynaptic material is observed within microglia by light microscopy, and this synapse engulfment is reduced in C3 or CR3 knockout mice.
“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).”
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Premisenone givenINPP5D encodes the lipid phosphatase SHIP1, which is preferentially expressed in microglia.
“INPP5D, which encodes the lipid phosphatase SHIP1, is another AD risk gene preferentially expressed in microglia.”
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PremisecitationProtective 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.
“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).”
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InterpretationcitationHuman microglia in aged brains or in the vicinity of tau pathology may exhibit dystrophic, fragmented morphology, suggesting that Alzheimer's disease develops in the context of reduced neuroprotective microglial function.
“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).”
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PremisecitationSHIP1 is involved in a clathrin-independent mode of receptor endocytosis and inhibits phagocytosis in macrophages.
“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).”
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- cites Cox et al., 2001
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PremisecitationSynapse pruning by microglia involves the classical complement pathway, with C1q tagging of synapses, opsonization by C3b, and subsequent phagocytosis by microglia.
“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).”
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PremisecitationMicroglia 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.
“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).”
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InterpretationcitationAlthough human genetic data argue that proper microglial function protects against Alzheimer's disease, there is plentiful evidence that unbridled microglia activity can be harmful to neurons in neurodegenerative disease.
“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.”
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PremisecitationWith β-amyloid deposition, some microglial processes become static, showing stable association with plaques over days or weeks, with TREM2, DAP12, and phosphotyrosine concentrated in processes adjacent to plaques.
“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).”
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PremisecitationThe microglial gene expression profile induced by amyloid pathology was broadly dampened in TREM2-deficient mice, indicating a key role of TREM2 in the microglial reaction to Aβ pathology.
“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).”
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PremisecitationAmyloid plaques appear a decade or two before clinical symptoms of Alzheimer's disease, but tau pathology and synapse loss correlate best with cognitive impairment during disease progression.
“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).”
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InterpretationreasoningIf the INPP5D genotype-expression relationship holds true in microglia, higher SHIP1 level would dampen microglial activation and phagocytosis and might explain the elevated Alzheimer's disease risk.
“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.”
Quote in the paperSubstantial claim- 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.
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PremisecitationGenetic knockout of C1q or neutralizing antibodies against C1q protect against synapse loss observed in amyloid-bearing mice or induced by injected Aβ.
“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).”
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- cites Hong et al., 2016 source
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PremisecitationThe PS19 study looked at 9 mo and observed preservation of piriform and entorhinal cortex volume in mice lacking TREM2, whereas tau phosphorylation and aggregation were unchanged.
“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).”
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PremisecitationTreatment with CSF1R inhibitors to deplete microglia or disable their proliferation protects against synapse loss and rescues behavioral deficits in amyloidosis mouse models.
“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).”
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- cites Spangenberg et al., 2016
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PremisecitationTrem2 deletion appears neuroprotective in the PS19 model but neurotoxic in the hTau model.
“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)”
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- cites Bemiller et al., 2017
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InterpretationcitationBesides the well-known effects of apoE4 on amyloid accumulation, apoE4 may contribute to AD pathogenesis by exacerbating neuroinflammation and tau pathology.
“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.”
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PremisecitationCx3cr1 knockout in amyloid models was reportedly accompanied by increased proinflammatory cytokines, tau pathology, and functional deficits.
“this was reportedly accompanied by increased proinflammatory cytokines, tau pathology, and functional deficits (Cho et al., 2011; Lee et al., 2014).”
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- cites Lee et al., 2014 source
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PremisecitationMouse models of β-amyloidosis exhibit elevated C1q levels, with increased synaptic localization of C1q even before plaques have formed.
“Mouse models of β-amyloidosis exhibit elevated C1q levels, with increased synaptic localization of C1q even before plaques have formed (Hong et al., 2016).”
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InterpretationreasoningMost 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.
“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).”
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PremisecitationC1q is expressed in the adult brain, and its protein levels rise steeply with aging, especially in the hippocampus.
“C1q is expressed in the adult brain, and protein levels rise steeply with aging, especially in the hippocampus (Stephan et al., 2013).”
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PremisecitationAlzheimer's disease-associated genes include CR1, which plays roles in phagocytosis, clearing immune complexes, and inhibition of complement, and CLU/apoJ, which can function as an inhibitor of the terminal complement complex.
“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).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Khera and Das, 2009
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- cites Fonseca et al., 2016 source
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- cites Murphy et al., 1989
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InterpretationcitationSynapse 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.
“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.”
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Premisecitationβ-Amyloid aggregates/fibrils can act as disease-associated molecular patterns and stimulate Toll-like receptors (TLRs) and the NRLP3 inflammasome, resulting in microglial production of TNFα, IL-1β, and other inflammatory cytokines.
“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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Heneka et al., 2013, 2015
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PremisecitationThe hTau study looked at 6 mo and observed greater tau phosphorylation and aggregation in TREM2-deficient mice, arguing for an early protective role of TREM2 in restraining propagation of tauopathy.
“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).”
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PremisecitationThese studies point to a disease-associated microglial (DAM) state in which expression of a "homeostatic" gene set is reduced and another set of "neurodegeneration" genes is highly induced.
“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).”
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PremisecitationRNA-sequencing studies of human microglia isolated from non-AD brain tissue 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.
“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.”
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- cites Gosselin et al., 2017 source
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Premisenone givenDAM cells increase in number with progression of amyloidosis, lie spatially close to amyloid plaque, and show evidence of Aβ uptake.
“Notably, DAM cells increase in number with progression of amyloidosis, lie spatially close to amyloid plaque, and show evidence of Aβ uptake.”
Quote in the paperNot a substantial claim
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?
Activated microglia and astrocytes can phagocytize Aβ through multiple receptors to protect neurons, but failure to clear aggregates leads to persistent chronic inflammation and release of proinflammatory/toxic products (cytokines, chemokines, ROS, NO), amplifying immune responses and neurotoxicity.
“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]
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Experimental — accuracy not yet measuredThe interaction of microglia within the complex brain microenvironment of Alzheimer's disease (e.g. neurons, astrocytes and amyloid-β plaques) is still not well explored.
“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]
The sections on synapse engulfment and neurotoxic inflammatory signaling discuss microglial interactions with neurons, astrocytes, and amyloid plaques. They do not characterize those interactions as generally 'not well explored'; the paper describes several specific mechanisms and findings instead. The copy provides no page numbers for these passages. (LLM, conf=0.78)
Experimental — accuracy not yet measuredIn the brain, PLCγ2 is primarily expressed by microglia, where it serves as an important signaling node downstream of TREM2 and CD33.
“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]
The section on other AD risk genes says PLCG2 is preferentially or selectively expressed in microglia, and the gene table places it downstream of SYK during ITAM signaling, consistent with a role in TREM2 signaling. It does not place PLCG2 downstream of CD33; the same section describes CD33 as an inhibitory receptor that opposes ITAM receptors and SYK. (LLM, conf=0.88)
Experimental — accuracy not yet measuredWithin the brain, PLCγ2 is primarily but not exclusively expressed in microglia, where it serves as an important signaling node downstream of TREM2 and CD33.
“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]
The section “Potential involvement of other AD risk genes in microglial function” says PLCG2 is preferentially expressed in microglia, and the table in “Human genetic evidence for microglia involvement in late-onset AD” places it downstream of SYK during ITAM signaling, consistent with the described TREM2 pathway. The paper instead describes CD33 as an inhibitory receptor that opposes ITAM receptors and SYK; it does not place PLCγ2 downstream of CD33. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredExtensive microglial activation promotes chronic neuroinflammation, which causes neuronal damage and is a major player in AD pathogenesis.
“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]
The “Microglia and neurotoxic inflammatory signaling” section says proinflammatory microglia can release mediators that harm neurons, and the Conclusion calls microglia crucial players in AD pathogenesis. But the conclusion describes their damaging role as supported mostly by mouse models and says an inflammatory state may correlate with neurodegeneration; it does not establish that extensive activation causes chronic neuroinflammation and neuronal damage as a general, settled account of AD. (LLM, conf=0.85)
Experimental — accuracy not yet measured
APOE ε4 disrupts lipid homeostasis and immune response and causes mitochondrial dysfunction.
“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]
The section on microglia and tau pathology reports heightened microglial response with apoE4 in a mouse model and suggests apoE4 may exacerbate neuroinflammation. The human-genetics section describes ApoE’s lipid-transport role, but does not establish that ε4 disrupts lipid homeostasis; neither passage establishes that ε4 causes mitochondrial dysfunction. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe disease-associated microglia signature includes downregulation of homeostatic microglia genes such as CX3CR1 and P2RY12 and upregulation of genes including APOE, AXL, SPP1, TREM2, and MHC-II.
“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]
The section “Microglial activation states defined by transcriptional profiling” (page not available in our copy) reports reduced Cx3cr1 and P2ry12, induced Apoe, Axl and some MHC-II genes, and modest increases in Trem2. It does not identify SPP1 as part of the DAM signature. The paper describes MHC-II in antigen presentation but does not state that it is essential for initiating an antigen-specific immune response. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMicroglia recognize Aβ oligomers via receptors such as CD36, TLR4, TLR6 and TREM2, acquiring specific AD-associated phenotypes.
“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]
The sections on phagocytosis and microglial activation report TREM2-dependent Aβ uptake and AD-associated microglial gene-expression changes. The inflammatory-signaling section says Aβ aggregates or fibrils stimulate Toll-like receptors, but our copy does not identify CD36, TLR4, or TLR6 as receptors for Aβ oligomers, or establish that recognition through this receptor list produces the stated phenotypes. The indexed passages provide section labels but no page numbers. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMicroglial cells maintain tissue homeostasis and keep the extracellular space clean of β-amyloid, thereby preventing Alzheimer's disease.
“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]
The Conclusion says microglia maintain tissue homeostasis and clear extracellular Aβ, thereby preventing AD, but explicitly presents this as a proposed hypothesis. The Introduction describes evidence for protective functions, so the citing sentence overstates the source by saying studies have shown the full prevention claim as fact. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe microglial response to amyloid plaques in Alzheimer's disease can range from neuroprotective to neurotoxic.
“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]
Human genetic studies suggest that reduced SPI1 expression may be protective against Alzheimer's disease.
“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]
In disease, microglial capacities can become either protective or damaging depending on context, timing, and molecular state.
“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 older binary language of resting versus activated microglia is too limited.
“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]
Alzheimer's disease risk can 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.
“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]
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.
“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]
Microglia are heavily implicated in the pathogenesis of AD.
“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]
Microglial cells are the main innate immune population residing in the CNS and play a critical role in CNS immune surveillance and tissue homeostasis through clearance of pathogens, dead cells, and protein aggregates such as Aβ.
“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]
Microglia dysfunction is suspected to be involved in AD through modulating Aβ aggregation/degradation.
“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]
Microglia are increasingly recognized as a central cell type contributing to AD etiology.
“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]
Inappropriate control of the classical complement cascade causes unresolvable inflammation and disease.
“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
Human AD involves impairments in microglial activation.
“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 neurodegenerative states, microglia can enhance neuroinflammation, leading to more cell deaths.
“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]
The capability of astrocytes and microglia to internalize and degrade Aβ is strictly correlated with their aberrant activation during Alzheimer's disease progression.
“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 a reactionary or dystrophic state, microglia contribute to the pathogenesis of various NDs and post-TBI syndromes.
“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]
Many, perhaps even a majority, of the genes contributing risk to AD are expressed primarily by microglia.
“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]
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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).”
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BackgroundIdentification of a unique TGF-β–dependent molecular and functional signature in microglia
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“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
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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.”
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“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
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Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease
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Microglial physiology: unique stimuli, specialized responses
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“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× · see citing works
“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× · see citing works
“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 · see citing works
Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways
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“…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 · see citing works
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× · see citing works
“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 1,227 · see citing works
An environment-dependent transcriptional network specifies human microglia identity
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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 · see citing works
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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× · see citing works
“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 · see citing works
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“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× · see citing works
“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× · see citing works
“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).”
BackgroundAlzheimer’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 · see citing works
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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 · see citing works
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× · see citing works
“…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× · see citing works
“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× · see citing works
“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., & Rothstein, J. (2006) · Nature Clinical Practice Neurology · doi:10.1038/ncpneuro0355 · Cited by 834 · cited 1× · see citing works
“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 · see citing works
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 · see citing works
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× · see citing works
“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× · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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× · see citing works
“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 · see citing works
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× · see citing works
“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 · see citing works
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× · see citing works
“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 · see citing works
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 · see citing works
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× · see citing works
“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 · see citing works
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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× · see citing works
“…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× · see citing works
“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 · see citing works
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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 · see citing works
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× · see citing works
“, 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 · see citing works
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× · see citing works
“…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× · see citing works
“…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).”
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 539 · cited 1× · see citing works
“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.”
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× · see citing works
“…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× · see citing works
“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).”
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 · see citing works
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× · see citing works
“, 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 · see citing works
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 · see citing works
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 · see citing works
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× · see citing works
“…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× · see citing works
“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).”
BackgroundProminent 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× · see citing works
“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 · see citing works
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× · see citing works
“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-citationMitochondrial 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 439 · see citing works
TREM2 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× · see citing works
“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 · see citing works
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× · see citing works
“…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 · see citing works
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× · see citing works
“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× · see citing works
“, 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 · see citing works
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× · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
Complement<i>C3</i>-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 · see citing works
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 364 · see citing works
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 362 · see citing works
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× · see citing works
“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× · see citing works
“…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 · see citing works
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× · see citing works
“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 · see citing works
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 · see citing works
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× · see citing works
“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× · see citing works
“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× · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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× · see citing works
“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 · see citing works
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 · see citing works
Liu, Z., Condello, C., Schain, A., Harb, R., & Grutzendler, J. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.4403-10.2010 · Cited by 276 · see citing works
Fonseca, 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× · see citing works
“, 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× · see citing works
“, 2010), this was reportedly accompanied by increased proinflammatory cytokines, tau pathology, and functional deficits (Cho et al., 2011; Lee et al., 2014).”
BackgroundBoyer, 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 263 · cited 1× · see citing works
“…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).”
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Alzheimer’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 · see citing works
Novel 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× · see citing works
“Interestingly, in knock-in mice expressing human apoE variants, the apoE4 risk allele increases C1q accumulation relative to apoE2 (Chung et al., 2016).”
BackgroundFleisher, 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 242 · see citing works
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 242 · cited 1× · see citing works
“…(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…”
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 · see citing works
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× · see citing works
“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).”
BackgroundEvidence 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 234 · cited 1× · see citing works
“…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.,…”
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 · see citing works
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 · see citing works
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× · see citing works
“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× · see citing works
“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× · see citing works
“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× · see citing works
“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 · see citing works
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× · see citing works
“Functions in the early endocytic pathway (Kajiho et al., 2011).”
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 · see citing works
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 181 · see citing works
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× · see citing works
“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× · see citing works
“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).”
BackgroundÇağlayan, Ş., Takagi‐Niidome, S., Liao, F., Carlo, A.-S., Schmidt, V., Burgert, T., Kitago, Y., Füchtbauer, E., Füchtbauer, A. C., Holtzman, D. M., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3007747 · Cited by 169 · see citing works
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 · see citing works
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× · see citing works
“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× · see citing works
“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× · see citing works
“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 · see citing works
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× · see citing works
“…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 · see citing works
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 · see citing works
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× · see citing works
“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 103 · cited 1× · see citing works
“…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 · see citing works
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 98 · see citing works
Degenerating Synaptic Boutons in Prion Disease
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Genetics of CD33 in Alzheimer's disease and acute myeloid leukemia
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“…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× · see citing works
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The Role of the Classical Complement Cascade in Synapse Loss During Development and Glaucoma
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“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 · see citing works
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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 · see citing works
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“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 · see citing works
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“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 · see citing works
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Inflammation in obesity, diabetes, and related disorders
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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 · see citing works
Microglia polarization from M1 to M2 in neurodegenerative diseases
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The Semantics of Microglia Activation: Neuroinflammation, Homeostasis, and Stress
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“Collectively, these studies point to neuroinflammation as a contributing factor in AD, however the precise role of microglia in AD is more complicated [69].”
BackgroundThe blood-brain barrier in aging and neurodegeneration
Knox, E. G., Aburto, M. R., Clarke, G., Cryan, J. F., & O’Driscoll, C. M. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01511-z · Cited by 738 · see citing works
Oxidative Stress and Antioxidants in Neurodegenerative Disorders
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The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway
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Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy
Muzio, L., Viotti, A., & Martino, G. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.742065 · Cited by 581 · see citing works
Amyloid-β-independent regulators of tau pathology in Alzheimer disease
van der Kant, R., Goldstein, L. S. B., & Ossenkoppele, R. (2020) · Nature reviews. Neuroscience · doi:10.1038/s41583-019-0240-3 · Cited by 580 · see citing works
Hippocampus and its involvement in Alzheimer’s disease: a review
Rao, Y. L., Ganaraja, B., Murlimanju, B. V., Joy, T., Krıshnamurthy, A., & Agrawal, A. (2022) · 3 Biotech · doi:10.1007/s13205-022-03123-4 · Cited by 577 · see citing works
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Self-citationAstrocytic and microglial cells as the modulators of neuroinflammation in Alzheimer’s disease
Singh, D. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02565-0 · Cited by 569 · see citing works
Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease
Roy, E. R., Wang, B., Wan, Y.-W., Chiu, G., Cole, A., Yin, Z., Propson, N. E., Xu, Y., Jankowsky, J. L., Liu, Z., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci133737 · Cited by 563 · see citing works
“In AD brain, microglia surrounding Aβ plaques switch into amoeboid morphology and assume an altered cellular state (40, 41).”
BackgroundAlzheimer’s disease: Recent treatment strategies
Vaz, M., & Silvestre, S. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173554 · Cited by 547 · see citing works
Hou, Y., Wei, Y. Q., Lautrup, S., Yang, B., Wang, Y., Cordonnier, S. A., Mattson, M. P., Croteau, D. L., & Bohr, V. A. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2011226118 · Cited by 545 · see citing works
“1B); and were all related to inflammation, immunity, and microglia (21).”
BackgroundMicroglial activation and tau propagate jointly across Braak stages
Pascoal, T. A., Benedet, A. L., Ashton, N. J., Kang, M. S., Therriault, J., Chamoun, M., Savard, M., Lussier, F. Z., Tissot, C., Karikari, T. K., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01456-w · Cited by 490 · see citing works
Gut microbiota and dysbiosis in Alzheimer's disease: Implications for pathogenesis and treatment
Liu, S., Gao, J., Zhu, M., Liu, K., & Zhang, H.-L. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-02073-3 · Cited by 516 · see citing works
“Microglial activation is associated with AD pathology [88] and phagocytic microglia are crucial for the uptake and engulfment of soluble Aβ species and the phagocytosis of insoluble fibrillar Aβ deposits [89].”
BackgroundWu, T., Dejanovic, B., Gandham, V. D., Gogineni, A., Edmonds, R., Schauer, S., Srinivasan, K., Huntley, M. A., Wang, Y., Wang, T.-M., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.07.060 · Cited by 466 · see citing works
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Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation
Srinivasan, K., Friedman, B. A., Etxeberria, A., Huntley, M. A., van der Brug, M. P., Foreman, O., Paw, J. S., Modrusan, Z., Beach, T. G., Serrano, G. E., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107843 · Cited by 427 · see citing works
“…could be that the DAM activation state in b-amyloid models is a protective response by healthy microglia (Keren-Shaul et al., 2017), whereas genetic and histological findings suggest that human AD involves impairments in microglial activation (Hansen et al., 2018; Streit et al., 2009).”
Self-citationHouldsworth, A. (2023) · Brain Communications · doi:10.1093/braincomms/fcad356 · Cited by 442 · see citing works
TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer's Disease
Griciuc, A., Patel, S., Federico, A. N., Choi, S. H., Innes, B. J., Oram, M. K., Cereghetti, G., McGinty, D., Anselmo, A., Sadreyev, R. I., et al. (2019) · Neuron · doi:10.1016/j.neuron.2019.06.010 · Cited by 378 · see citing works
“While microglia can clear amyloid beta (Aβ), they can also release pro-inflammatory cytokines leading to neuroinflammation (Hansen et al., 2018; Hickman et al., 2008).”
Energy metabolism in health and diseases
Liu, H., Wang, S., Wang, J., Guo, X., Song, Y., Fu, K., Gao, Z., Liu, D., He, W., & Yang, L. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02141-x · Cited by 438 · see citing works
Integrated multimodal cell atlas of Alzheimer’s disease
Gabitto, M. I., Travaglini, K. J., Rachleff, V. M., Kaplan, E. S., Long, B., Ariza, J., Ding, Y., Mahoney, J. T., Dee, N., Goldy, J., et al. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01774-5 · Cited by 397 · see citing works
An Activity-Guided Map of Electrophile-Cysteine Interactions in Primary Human T Cells
Vinogradova, E. V., Zhang, X., Remillard, D., Lazar, D. C., Suciu, R. M., Wang, Y., Bianco, G., Yamashita, Y., Crowley, V. M., Schafroth, M. A., et al. (2020) · Cell · doi:10.1016/j.cell.2020.07.001 · Cited by 351 · see citing works
“Human genetics has emphasized the central role that the immune system plays as both a causal basis for and guardian against a broad range of diseases (Hansen et al., 2018; Lucherini et al., 2018; Sims et al., 2017).”
Zhong, L., Xu, Y., Zhuo, R., Wang, T., Wang, K., Huang, R., Wang, D., Gao, Y., Zhu, Y., Sheng, X., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09118-9 · Cited by 371 · see citing works
A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease
Hampel, H., Caraci, F., Cuello, A. C., Caruso, G., Nisticò, R., Corbo, M., Baldacci, F., Toschi, N., Garaci, F., Chiesa, P. A., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00456 · Cited by 360 · see citing works
Microbiota-derived short chain fatty acids modulate microglia and promote Aβ plaque deposition
Colombo, A. V., Sadler, R. K., Llovera, G., Singh, V., Roth, S., Heindl, S., Sebastian Monasor, L., Verhoeven, A., Peters, F., Parhizkar, S., et al. (2021) · eLife · doi:10.7554/elife.59826 · Cited by 354 · see citing works
“In particular, triggering microglial phagocytic clearance of Ab can reduce amyloid plaque pathology (Daria et al., 2017; Hansen et al., 2018).”
BackgroundInvolvement of Lipids in Alzheimer’s Disease Pathology and Potential Therapies
Chew, H., Solomon, V. A., & Fonteh, A. N. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00598 · Cited by 353 · see citing works
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“Another explanation is that, the activation of healthy microglia is likely more beneficial in the early stage of AD models, whereas microglial activation in human AD involves impairments (15, 41).”
BackgroundDejanovic, B., Wu, T., Tsai, M.-C., Graykowski, D., Gandham, V. D., Rose, C. M., Bakalarski, C. E., Ngu, H., Wang, Y., Pandey, S., et al. (2022) · Nature Aging · doi:10.1038/s43587-022-00281-1 · Cited by 341 · see citing works
Self-citationThe role of astroglia in Alzheimer's disease: pathophysiology and clinical implications
Arranz, A. M., & Strooper, B. D. (2019) · The Lancet Neurology · doi:10.1016/s1474-4422(18)30490-3 · Cited by 348 · see citing works
Microglia Phenotypes in Aging and Neurodegenerative Diseases
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Microglia in Alzheimer's disease at single-cell level. Are there common patterns in humans and mice?
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“However, excessive activation of microglial proinflammatory functionsmay be detrimental and accelerate tissue damage (Hansen et al., 2018; Villacampa and Heneka, 2020).”
BackgroundMonteiro, A. R., Barbosa, D. J., Remião, F., & Silva, R. V. D. S. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2023.115522 · Cited by 358 · see citing works
<i>APOE4</i> disrupts intracellular lipid homeostasis in human iPSC-derived glia
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Phagocytosis in the Brain: Homeostasis and Disease
Galloway, D. A., Phillips, A. E. M., Owen, D. R., & Moore, C. S. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00790 · Cited by 304 · see citing works
Neuroinflammation in Alzheimer’s Disease
Onyango, I. G., Jauregui, G. V., Čarná, M., Bennett, J. P., & Stokin, G. B. (2021) · Biomedicines · doi:10.3390/biomedicines9050524 · Cited by 330 · see citing works
“Initially, microglial activation may serve to eliminate Aβ [126,133–135], but their chronic activation may amplify the amyloid cascade [133,136] and lead to neurotoxicity [137,138].”
BackgroundSey, N. Y. A., Hu, B., Mah, W., Fauni, H., McAfee, J. C., Rajarajan, P., Brennand, K. J., Akbarian, S., & Won, H. (2020) · Nature Neuroscience · doi:10.1038/s41593-020-0603-0 · Cited by 297 · see citing works
Microglia in Alzheimer’s disease: pathogenesis, mechanisms, and therapeutic potentials
Miao, J., Ma, H., Yang, Y., Liao, Y., Lin, C., Zheng, J., Yu, M., & Lan, J. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1201982 · Cited by 293 · see citing works
“Furthermore, as AD progresses, microglia’s ability to phagocytose Aβ plaques decreases, leading to their accumulation in the brain and further AD progression (Hansen et al., 2018).”
BackgroundInfluentialMicroglia and the aging brain: are senescent microglia the key to neurodegeneration?
Angelova, D. M., & Brown, D. R. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14860 · Cited by 262 · see citing works
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Conservation and divergence of cortical cell organization in human and mouse revealed by MERFISH
Fang, R., Xia, C., Close, J. L., Zhang, M., He, J., Huang, Z., Halpern, A. R., Long, B., Miller, J. A., Lein, E. S., et al. (2022) · Science · doi:10.1126/science.abm1741 · Cited by 277 · see citing works
“Satellite microglia can help maintain tissue homeostasis (38) and human genetics evidences suggest that microglia play a protective role that lowers the incidence of some neurodegenerative diseases (39).”
BackgroundGovindpani, K., McNamara, L. G., Smith, N. R., Vinnakota, C., Waldvogel, H. J., Faull, R. L. M., & Kwakowsky, A. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8050651 · Cited by 271 · see citing works
“Activated microglia likely play a protective role in the AD brain, being found around Aβ plaques and possibly being involved in their immunological isolation from the surrounding parenchyma [209,210].”
BackgroundInfluentialMicroglia in Alzheimer Disease: Well-Known Targets and New Opportunities
Hemonnot, A.-L., Hua, J., Ulmann, L., & Hirbec, H. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00233 · Cited by 298 · see citing works
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Innate Immune Cell Death in Neuroinflammation and Alzheimer’s Disease
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Hussain, B., Fang, C., & Chang, J. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.688090 · Cited by 251 · see citing works
Homeostasis and metabolism of iron and other metal ions in neurodegenerative diseases
Chen, L., Shen, Q., Liu, Y., Zhang, Y., Sun, L., Ma, X., Song, N., & Xie, J. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02071-0 · Cited by 271 · see citing works
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Microglia in Brain Development, Homeostasis, and Neurodegeneration
Bohlen, C. J., Friedman, B. A., Dejanovic, B., & Sheng, M. (2019) · Annual Review of Genetics · doi:10.1146/annurev-genet-112618-043515 · Cited by 212 · see citing works
Self-citationCien Años de Microglía: Milestones in a Century of Microglial Research
Sierra, A., Paolicelli, R. C., & Kettenmann, H. (2019) · Trends in Neurosciences · doi:10.1016/j.tins.2019.09.004 · Cited by 229 · see citing works
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Gut Microbiota and Their Neuroinflammatory Implications in Alzheimer’s Disease
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Microglia in Alzheimer’s Disease: Activated, Dysfunctional or Degenerative
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“These GWAS analysis have identified multiple polymorphisms associated with the microglial immune response (Guerreiro et al., 2013; Cuyvers and Sleegers, 2016; Hansen et al., 2018).”
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Tau Protein Interaction Partners and Their Roles in Alzheimer’s Disease and Other Tauopathies
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Emerging Microglia Biology Defines Novel Therapeutic Approaches for Alzheimer’s Disease
Lewcock, J. W., Schlepckow, K., Di Paolo, G., Tahirovic, S., Monroe, K. M., & Haass, C. (2020) · Neuron · doi:10.1016/j.neuron.2020.09.029 · Cited by 221 · see citing works
Long‐COVID syndrome‐associated brain fog and chemofog: Luteolin to the rescue
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Intersection of pathological tau and microglia at the synapse
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CXCR6 orchestrates brain CD8+ T cell residency and limits mouse Alzheimer’s disease pathology
Su, W., Saravia, J., Risch, I., Rankin, S. L., Guy, C. S., Chapman, N. M., Shi, H., Sun, Y., Anil, K. C., Li, W., et al. (2023) · Nature Immunology · doi:10.1038/s41590-023-01604-z · Cited by 216 · see citing works
Effects of curcumin on mitochondria in neurodegenerative diseases
Bagheri, H., Ghasemi, F., Barreto, G. E., Rafiee, R., Sathyapalan, T., & Sahebkar, A. (2019) · BioFactors · doi:10.1002/biof.1566 · Cited by 211 · see citing works
“The chronic expression of several compounds such as TNF-α, IL-1β, PGE2, IL-6, IFN-γ, ROS, and RNS could be destructive to cells.(2,110) Long-standing neuroinflammation and chronic expression of several compounds will strikingly affect the neuronal viability and the survival of neural precursor cells by unbalancing the…”
BackgroundLi, Z., Song, Y., He, T., Wen, R., Li, Y.-F., Chen, T., Huang, S., Wang, Y., Tang, Y., Shen, F., et al. (2020) · Theranostics · doi:10.7150/thno.48761 · Cited by 210 · see citing works
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Self-citationInflammatory biomarkers in Alzheimer's disease plasma
Morgan, A. R., Touchard, S., Leckey, C. A., O’Hagan, C., Nevado‐Holgado, A. J., Barkhof, F., Bertram, L., Blin, O. J., Bos, I., Dobričić, V., et al. (2019) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2019.03.007 · Cited by 207 · see citing works
“This finding resonates with preclinical data suggesting that complement and microglial activation play important roles as mediators of neurotoxicity in AD [46].”
ResultiPSC-based disease modeling and drug discovery in cardinal neurodegenerative disorders
Okano, H., & Morimoto, S. (2022) · Cell stem cell · doi:10.1016/j.stem.2022.01.007 · Cited by 203 · see citing works
Updates in Alzheimer's disease: from basic research to diagnosis and therapies
Liu, E., Zhang, Y., & Wang, J. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00432-x · Cited by 220 · see citing works
“Activated microglia are found surrounding senile plaques in the brains of AD patients [144].”
BackgroundGlial Cell-Mediated Neuroinflammation in Alzheimer’s Disease
Al-Ghraiybah, N. F., Wang, J., Alkhalifa, A. E., Roberts, A. B., Raj, R., Yang, E., & Kaddoumi, A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231810572 · Cited by 204 · see citing works
“The overactivation of microglia adopts them to the reactive states [83], characterized by significant phenotypic and morphology changes accompanied by elevated expression of the pro-inflammatory cytokines TNFα, IL-6, IL-1β, and NO [83,84].”
BackgroundTargeting toll-like receptor 4 to modulate neuroinflammation in central nervous system disorders
Leitner, G. R., Wenzel, T., Marshall, N., Gates, E. J., & Klegeris, A. (2019) · Expert opinion on therapeutic targets · doi:10.1080/14728222.2019.1676416 · Cited by 187 · see citing works
Peripheral inflammatory biomarkers in Alzheimer’s disease: a brief review
Park, J., Han, S.-H., & Mook‐Jung, I. (2020) · BMB Reports · doi:10.5483/bmbrep.2020.53.1.309 · Cited by 200 · see citing works
“Activated microglia are one of the early hallmarks of AD pathogenesis (3).”
BackgroundApolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease
Najm, R., Jones, E. A., & Huang, Y. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0324-6 · Cited by 183 · see citing works
Sevenich, L. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00697 · Cited by 199 · see citing works
Microglial Piezo1 senses Aβ fibril stiffness to restrict Alzheimer’s disease
Hu, J., Chen, Q., Zhu, H., Hou, L., Liu, W., Yang, Q., Shen, H., Chai, G., Zhang, B., Chen, S., et al. (2022) · Neuron · doi:10.1016/j.neuron.2022.10.021 · Cited by 196 · see citing works
Wang, Y., Lin, Y., Wang, L., Zhan, H., Luo, X., Zeng, Y., Wu, W., Zhang, X., & Wang, F. (2020) · Aging · doi:10.18632/aging.104104 · Cited by 196 · see citing works
Probiotics for Alzheimer’s Disease: A Systematic Review
Naomi, R., Embong, H., Othman, F., Ghazi, H. F., Maruthey, N., & Bahari, H. (2021) · Nutrients · doi:10.3390/nu14010020 · Cited by 200 · see citing works
“Evidence suggests that reactive microglia provide a protective barrier around amyloid deposits, preventing the accumulation of new Aβ onto existing plaques [30].”
BackgroundXu, R., Li, X., Boreland, A. J., Posyton, A., Kwan, K. Y., Hart, R. P., & Jiang, P. (2020) · Nature Communications · doi:10.1038/s41467-020-15411-9 · Cited by 190 · see citing works
β-Amyloid Clustering around ASC Fibrils Boosts Its Toxicity in Microglia
Friker, L. L., Scheiblich, H., Hochheiser, I. V., Brinkschulte, R., Riedel, D., Latz, E., Geyer, M., & Heneka, M. T. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.02.025 · Cited by 191 · see citing works
“Altogether, these findings reveal a possible mechanism involved in AD progression because Ab plaque clearance bymicroglia is essentially important in the disease context (Hansen et al., 2018; Sarlus and Heneka, 2017).”
BackgroundTREM2 dependent and independent functions of microglia in Alzheimer’s disease
Hou, J., Chen, Y., Grajales-Reyes, G., & Colonna, M. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00588-y · Cited by 191 · see citing works
“Initial studies of microglia responses to AD pathology During AD, the brain environment becomes highly perturbed locally, which leads to “reactive microgliosis”, characterized by microglia proliferation with a hypertrophic or ameboid shape [46].”
BackgroundThe link between chronic pain and Alzheimer’s disease
Cao, S., Fisher, D. W., Yu, T., & Dong, H. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1608-z · Cited by 183 · see citing works
“In fact, reactivations of microglia and neuroinflammation are now considered characteristics of AD pathogenesis [111].”
BackgroundProfiling senescent cells in human brains reveals neurons with CDKN2D/p19 and tau neuropathology
Dehkordi, S. K., Walker, J., Sah, E., Bennett, E., Atrian, F., Frost, B., Woost, B., Bennett, R. E., Orr, T. C., Zhou, Y., et al. (2021) · Nature Aging · doi:10.1038/s43587-021-00142-3 · Cited by 169 · see citing works
Mitochondrial Dysfunction and Alzheimer’s Disease: Role of Microglia
Agrawal, I., & Jha, S. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00252 · Cited by 181 · see citing works
Jin, M., Xu, R., Wang, L., Alam, M. M., Ma, Z., Zhu, S., Martini, A. C., Jadali, A., Bernabucci, M., Xie, P., et al. (2022) · Cell Stem Cell · doi:10.1016/j.stem.2022.06.007 · Cited by 174 · see citing works
Single-cell DNA methylation and 3D genome architecture in the human brain
Tian, W., Zhou, J., Bartlett, A., Zeng, Q., Liu, H., Castanon, R. G., Kenworthy, M., Altshul, J., Valadon, C., Aldridge, A., et al. (2023) · Science · doi:10.1126/science.adf5357 · Cited by 154 · see citing works
“Collectively, these analyses revealed the cell-type specificity of chromatin architecture and its relationship with other epigenomic and transcriptomic signatures at an unprecedented cell-type resolution in the human brain.”
BackgroundAlzheimer's Disease Puzzle: Delving into Pathogenesis Hypotheses
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Microglia regulation of central nervous system myelin health and regeneration
Kent, S. A., & Miron, V. E. (2024) · Nature Reviews Immunology · doi:10.1038/s41577-023-00907-4 · Cited by 183 · see citing works
“Second, microglia are also heavily implicated in the pathology of Alzheimer disease (AD) 25 , which is characterized by pathological accumulation of amyloid-β plaques and neurofibrillary tau tangles that leads to loss of neurons and their synapses.”
Dourlen, P., Kilinc, D., Malmanche, N., Chapuis, J., & Lambert, J.-C. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02004-0 · Cited by 168 · see citing works
“Indeed, several genomic analyses suggest the involvement of microglia in AD: (1) the first reports on pathway enrichment analyses indicated the involvement of innate immunity in AD [81]; (2) as previously mentioned, these analyses highlighted the regulation of endocytosis (which is essential for phagocytosis) [64, 81]…”
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“disease, protective microglial activities supposedly occur in the early disease stages [10].”
BackgroundHuman Microglia Show Unique Transcriptional Changes in Alzheimer's Disease
Prater, K. E., Green, K. J., Mamde, S., Sun, W., Cochoit, A., Smith, C. L., Chiou, K. L., Heath, L., Rose, S. E., Wiley, J., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00424-y · Cited by 164 · see citing works
Ubiquitin Ligase COP1 Suppresses Neuroinflammation by Degrading c/EBPβ in Microglia
Ndoja, A., Reja, R., Lee, S.-H., Webster, J. D., Ngu, H., Rose, C. M., Kirkpatrick, D. S., Modrusan, Z. D., Chen, Y.-J. J., Dugger, D. L., et al. (2020) · Cell · doi:10.1016/j.cell.2020.07.011 · Cited by 160 · see citing works
Targeting synapse function and loss for treatment of neurodegenerative diseases
Dejanovic, B., Sheng, M., & Hanson, J. E. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00823-1 · Cited by 168 · see citing works
“In AD, for instance, most risk genes are significantly enriched or selectively expressed in microglia 31 .”
Self-citationMicroRNAs in Alzheimer's disease: Potential diagnostic markers and therapeutic targets
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“Neuroinflammatory changes around the amyloid plaques include reactive astrocytosis and microglial cell activation [3].”
BackgroundAlzheimer’s Disease Pathogenesis: Role of Autophagy and Mitophagy Focusing in Microglia
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“This may be explained by the detection by mMCP-counter of microglia, which have been shown to be a prominent marker of AD [32].”
BackgroundGut microbiome-targeted therapies for Alzheimer’s disease
Zhang, T., Gao, G., Kwok, L., & Sun, Z. (2023) · Gut Microbes · doi:10.1080/19490976.2023.2271613 · Cited by 153 · see citing works
“In AD, dynamic changes in microglial activation can affect disease progression 31,32 , playing a central role for promoting disease pathogenesis.”
BackgroundTranslating genetic risk of Alzheimer’s disease into mechanistic insight and drug targets
Sierksma, A. S. R., Escott‐Price, V., & Strooper, B. D. (2020) · Science · doi:10.1126/science.abb8575 · Cited by 149 · see citing works
“The rare R47H and more common R62H variants of TREM2 ( 15 ) alter its stability, affect phagocytic capacity and impair TREM2 affinity for APOE, clusterin (ApoJ), low-density lipoproteins (LDL) and Aβ ( 33 ).”
Microglial inflammation and phagocytosis in Alzheimer's disease: Potential therapeutic targets
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“driven towards a chronic inflammatory state, in response to cues such as excessive neuron death (Hansen et al., 2018).”
Background
- 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
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- microglia, Alzheimer's disease, microglial activation, amyloid plaques, amyloid-beta, risk genes, synaptic loss, tau pathology, neuroinflammation, astrocyte activation, microglial activation states, neurodegeneration
- MeSH terms
- Alzheimer Disease, Animals, Brain, Humans, Microglia
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