TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy
Open accessAbstract
Haplodeficiency of the microglia gene TREM2 increases risk for late-onset Alzheimer's disease (AD) but the mechanisms remain uncertain. To investigate this, we used high-resolution confocal and super-resolution (STORM) microscopy in AD-like mice and human AD tissue. We found that microglia processes, rich in TREM2, tightly surround early amyloid fibrils and plaques promoting their compaction and insulation. In Trem2- or DAP12-haplodeficient mice and in humans with R47H TREM2 mutations, microglia had a markedly reduced ability to envelop amyloid deposits. This led to an increase in less compact plaques with longer and branched amyloid fibrils resulting in greater surface exposure to adjacent neurites. This was associated with more severe neuritic tau hyperphosphorylation and axonal dystrophy around amyloid deposits. Thus, TREM2 deficiency may disrupt the formation of a neuroprotective microglia barrier that regulates amyloid compaction and insulation. Pharmacological modulation of this barrier could be a novel therapeutic strategy for AD.
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Microglial phagocytosis is important for plaque remodeling and Aβ clearance.
“Microglial phagocytosis is important for plaque remodeling and A β clearance 28 .”
From Genetic variants of phospholipase C-γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer’s disease (2023) · cites this paper as [28]
The Introduction (page unavailable) says microglia were traditionally thought to clear Aβ by phagocytosis, but cites evidence that they are ineffective at removing fibrillar Aβ in vivo. The Results section on Aβ phagocytosis (page unavailable) attributes altered plaque structure in Trem2 haplodeficiency to impaired microglial barrier formation, while Aβ phagocytosis remains unchanged. The paper therefore does not identify phagocytosis as the mechanism of plaque remodeling or effective fibrillar Aβ clearance. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredAPOE2 promotes plaque compaction and limits diffusion of toxic Aβ species.
“suggesting that APOE2 promotesplaquecompactionandlimitsdiffusion of toxicA β species 47 .”
From APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease (2026) · cites this paper as [47]
The Results section (page not provided) finds that TREM2 deficiency reduces plaque compaction and allows Aβ fibrils to extend outward; the Discussion associates less compact fibrils with greater toxicity. But the Discussion only speculates that ApoE polymorphisms might affect the microglial barrier. It does not identify an APOE2 effect or show that APOE2 limits diffusion of toxic Aβ species. (LLM, conf=0.82)
Experimental — accuracy not yet measuredRecent in vivo studies suggest TREM2 may be protective or damaging depending on the pathological stage.
“recent in vivo studies suggest that TREM2 may be protective or damaging depending on the pathological stage [19,30,31,32].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [32]
The Discussion (page unavailable) describes a potentially neuroprotective TREM2-dependent microglial barrier around amyloid plaques. It does not report that TREM2 becomes damaging at another pathological stage, so it supports the protective possibility but not the proposed stage-dependent reversal. (LLM, conf=0.85)
Experimental — accuracy not yet measuredGenetically decreasing TREM2 levels or altering its function in transgenic mice with amyloid plaque deposits injected with human AD brain-derived tau aggregates enhances tau propagation.
“Genetically decreasing TREM2 levels or altering its function in transgenic mice with amyloid plaque deposits injected with human AD brain-derived tau aggregates enhances tau propagation [19,30,31,32,39,40].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [32]
The Abstract and Discussion report TREM2-deficient mice with amyloid plaques and increased neuritic tau hyperphosphorylation around plaques. The paper does not report injecting human AD brain-derived tau aggregates into those mice or measuring enhanced tau propagation; those are distinct parts of the attributed claim. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe microenvironment in Aβ plaques plays a crucial role in Aβ-mediated neuroinflammation and tau pathogenesis in AD mouse models.
“Moreover, the microenvironment in Aβ plaques plays a crucial role in Aβ-mediated neuroinflammation and tau pathogenesis in AD mouse models [34, 53, 106].”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [106]
The Results and Discussion (pages unavailable) show that microglial coverage and plaque compaction affect axonal dystrophy in AD-like mice, supporting a role for the local plaque environment in neural damage. The cited paper does not establish that this environment drives Aβ-mediated neuroinflammation, and its direct phosphotau findings concern human AD brains rather than tau pathogenesis in the mouse models. (LLM, conf=0.85)
Experimental — accuracy not yet measured
In the context of AD or aging, the formation of filamentous plaques has been associated with the phosphorylation of tau within dystrophic neurites.
“In the context of AD or aging, the formation of filamentous plaques has been associated with the phosphorylation of tau within dystrophic neuritis [13, 53, 106], which subsequently contributes to the formation of neuritic plaques (a subset of Aβ plaques surrounded by and containing dystrophic neurites) during AD progression”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [106]
The Results section on tau hyperphosphorylation and axonal dystrophy reports phosphotau-positive dystrophic neurites around filamentous amyloid plaques in human AD brains. This supports the association in AD, but the paper does not establish it in aging apart from AD. (LLM, conf=0.83)
Experimental — accuracy not yet measuredPhosphorylation of tau within dystrophic neurites subsequently contributes to the formation of neuritic plaques during AD progression.
“In the context of AD or aging, the formation of filamentous plaques has been associated with the phosphorylation of tau within dystrophic neuritis [13, 53, 106], which subsequently contributes to the formation of neuritic plaques (a subset of Aβ plaques surrounded by and containing dystrophic neurites) during AD progression”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [106]
The Results section on tau hyperphosphorylation (page unavailable) reports phospho-tau labeling in dystrophic neurites around filamentous and compact amyloid deposits. It does not show that tau phosphorylation contributes to plaque formation; the Discussion instead describes filamentous plaques as causing axonal dystrophy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMicroglia limit diffuse plaques by constructing and maintaining dense compact-like plaque properties in AD mouse models and humans, thereby blocking the progression of neuritic dystrophy and reducing tau phosphorylation in the local plaque environment.
“Furthermore, microglia limit diffuse plaques by constructing and maintaining dense compact-like plaque properties in AD mouse models and humans, thereby blocking the progression of neuritic dystrophy and reducing tau phosphorylation in the local plaque environment [12, 38, 106].”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [106]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredMurine microglia lacking TREM2 have deficient responses to Aβ and impaired acquisition of the neuroprotective disease-associated microglia (DAM) phenotype.
“Murine microglia lacking TREM2 have deficient responses to Aβ and impaired acquisition of the neuroprotective disease‐associated microglia (DAM) phenotype.”
From PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology (2025) · cites this paper as [41]
The Results section reports that Trem2-deficient mouse microglia have impaired process polarization toward Aβ plaques and reduced plaque coverage, supporting a deficient response to Aβ. The paper describes this as a failure of the potentially neuroprotective microglial barrier; it does not establish impaired acquisition of a disease-associated microglia (DAM) phenotype. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTREM2 deletion reduces microglial survival and phagocytosis in vitro and impacts plaque pathology across disease progression in amyloidogenic mouse models.
“TREM2 deletion reduces microglial survival and phagocytosis in vitro and impacts plaque pathology across disease progression in amyloidogenic mouse models.”
From PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology (2025) · cites this paper as [41]
The Results section ('Microglia processes envelop individual fibrils in early filamentous plaques'; page unavailable) reports that Trem2-deficient AD-like mice had a higher proportion of filamentous plaques, supporting an effect on plaque pathology. The Introduction cites prior in-vitro evidence of disrupted Aβ phagocytosis, and the Discussion reports reduced phagocytosis with complete Trem2 loss in vivo, not an in-vitro test by this study. Our copy does not establish reduced microglial survival or effects measured across disease progression. (LLM, conf=0.86)
Experimental — accuracy not yet measuredTREM2 deficiency results in higher deposition of amyloid in the hippocampus of 5XFAD mice and reduces recruitment of microglia to plaques.
“TREM2 deficiency has been reported to result in a higher deposition of amyloid in the hippocampus of 5XFAD mice, and was found to reduce the recruitment of microglia to plaques [16, 50]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [16]
The Results section ('Trem2 haplodeficiency abolishes the microglia barrier') reports about 20% fewer plaque-associated microglia with Trem2 deficiency, supporting reduced recruitment to plaques. But the Results section on plaque compaction finds no significant difference in total plaque number, and the cited passages do not establish higher amyloid deposition specifically in the hippocampus of 5XFAD mice. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTREM2-deficient microglia show reduced uptake of Aβ complex in vitro and less Aβ internalisation in vivo.
“TREM2-deficient microglia show reduced uptake of Aβ complex in vitro and less Aβ internalisation in vivo [150, 154].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [154]
The Introduction reports earlier in vitro work finding disrupted Aβ phagocytosis after Trem2 loss. The Results section, ‘Trem2 haplodeficiency abolishes the microglia barrier but does not impair Aβ phagocytosis,’ finds reduced Aβ in microglial phagosomes in vivo in Trem2−/− mice, but not in Trem2+/− mice. The claim omits that distinction and the paper does not specify uptake of an Aβ complex in vitro. (LLM, conf=0.85)
Experimental — accuracy not yet measuredTREM2 is protective, and AD-associated mutations R47H and R62H likely impair its physiological functions in phagocytosis and clearance of Aβ peptides and in compaction of amyloid plaques and barrier formation.
“TREM2 has been proposed to be protective, since the AD-associated mutations (R47H, R62H) likely impair its physiological functions at two levels: (1) phagocytosis and clearance of Aβ peptides and (2) compaction of amyloid plaques and barrier formation.”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [154]
The Introduction and Results report that TREM2 helps form a protective microglial barrier that promotes plaque compaction, and that this function is impaired in people with R47H. But the Results and Discussion say Aβ phagocytosis remained normal in the haplodeficient mice used to model the AD-associated mutation; the paper does not establish impaired Aβ clearance or address R62H. (LLM, conf=0.89)
Experimental — accuracy not yet measuredThe work adds evidence that the microglial response in late-onset Alzheimer's disease is directly causal rather than merely a downstream consequence of neurodegeneration.
“This work provides additional evidence that the microglial response in LOAD is directly part of a causal pathway leading to disease and is not simply a downstream consequence of neurodegeneration46,47,57,58.”
From Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease (2017) · cites this paper as [58]
Impaired microglial barrier formation has been shown to reduce plaque compaction and increase the exposure of surrounding neurites to fibrillar Aβ, resulting in greater neuritic dystrophy.
“In contrast, impaired microglial barrier formation has been shown to reduce plaque compaction and increase the exposure of surrounding neurites to fi brillar A β , resulting in greater neuritic dystrophy 47 .”
From APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease (2026) · cites this paper as [47]
Increased association of microglia with plaques reduces neuritic dystrophy.
“Further, increased association of microglia with plaques reduces neuritic dystrophy.63”
From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [63]
Reactive microglia form a physical barrier believed to restrict plaque propagation.
“form a physical barrier believed to restrict plaque propagation13,14”
From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [14]
Prior studies proposed that plaque-associated microglia compact amyloid plaques through receptors implicated in phagocytosis such as TREM2, AXL, and MER.
“Prior studies proposed that these cells compact amyloid plaques through receptors implicated in phagocytosis such as TREM214, (expressed on myeloid cells and associated to increased AD risk)14,8, AXL, and MER79.”
From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [14]
Genetic deletion of any of these receptors in mouse models of AD results in less compact/more diffuse plaques, and increased neuritic dystrophy around Aβ deposits.
“Genetic deletion of any of these receptors in mouse models of AD resulted in less compact/more diffuse plaques, and increased neuritic dystrophy around Αβ deposits14,79.”
From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [14]
Less microglia surrounding plaques were detected in Abi3−/− mice, similar to Trem2 knockout mice.
“Supporting this hypothesis, we detected less microglia surrounding the plaques in Abi3−/− mice, similar to what has been observed in Trem2 knockout (Trem2−/−) mice (45, 46).”
From Deletion of <i>Abi3</i> gene locus exacerbates neuropathological features of Alzheimer’s disease in a mouse model of Aβ amyloidosis (2021) · cites this paper as [45]
Deletion of Trem2 impairs microglia clustering around Aβ plaques.
“many studies demonstrated that deletion of Trem2 impairs microglia clustering around Aβ plaques (45, 46).”
From Deletion of <i>Abi3</i> gene locus exacerbates neuropathological features of Alzheimer’s disease in a mouse model of Aβ amyloidosis (2021) · cites this paper as [45]
Similar observation was made in human Alzheimer's disease brain with TREM2 R47H mutation.
“Similar observation was also made in human Alzheimer's disease brain with TREM2 R47H mutation [38].”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [38]
TREM2 deficiency results in a decreased ratio of compact region versus diffused region of plaques.
“TREM2 deficiency results in the decreased ratio of compact region versus diffused region of plaques [38,39].”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [38]
In Trem2 or Dap12 haplodeficient mice and humans carrying the R47H mutation in the TREM2 gene, microglia demonstrate a markedly reduced ability to envelop amyloid deposits, decreasing compact plaque phenotypes and increasing amyloid fibril exposure to adjacent neurites, which is associated with tau hyperphosphorylation.
“In Trem2 or Dap12 haplodeficient mice and humans carrying the R47H mutation in the TREM2 gene, the microglia demonstrate a markedly reduced ability to envelop amyloid deposits, decreasing compact plaque phenotypes and increasing amyloid fibril exposure to adjacent neurites, which is associated with tau hyperphosphorylation [102, 106].”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [106]
Previous reports suggest that plaque morphology, rather than total amyloid burden, may be a key factor in neurotoxicity and disease progression.
“These findings align with previous reports suggesting that plaque morphology, rather than total amyloid burden, may be a key factor in neurotoxicity and disease progression and suggest that this could be an important role for plaque‐associated PLCγ2 expressing microglia (Casali et al. 2020; Shi et al. 2017; Yuan et al. 2016).”
From Alzheimer's Protection by <scp>PLCγ2</scp> Compacts Plaques, Redistributes Microglia, and Protects Synapses in <scp> <i>App</i> <sup> <i>NL</i> </sup> </scp> <sup> <i>‐G‐F</i> </sup> Mice (2026) · cites this paper as Yuan et al. 2016
Microglia from individuals carrying the TREM2 R47H mutation failed to surround Aβ plaques, which correlated with an increase in filamentous amyloid deposits and phospho-tau-positive neurites in the brain.
“microglia from individuals carrying the TREM2 R47H mutation failed to surround Aβ plaques, which correlated with an increase in filamentous amyloid deposits and phospho-tau-positive neurites in the brain [16, 103]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [16]
Microglia form a protective barrier around Aβ plaques to safeguard the brain from their neurotoxic effects.
“Microglia form a protective barrier around these Aβ plaques to safeguard the brain from their neurotoxic effects (15, 16).”
From Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model (2025) · cites this paper as [15]
Microglia form a protective barrier around amyloid deposits by compacting amyloid fibrils into a potentially less toxic form, and this mechanism is less efficient in AD-like models underexpressing TREM2.
“microglia have been recently suggested to form a protective barrier around amyloid deposits by compacting amyloid fibrils into a potentially less toxic form [154]. This protective mechanism appears to be less efficient in AD-like models underexpressing TREM2.”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [154]
This neuronal cluster may represent dystrophic neurons that accumulate over time because microglial control of Alzheimer's pathology is ineffective without Trem2.
“which may represent dystrophic neurons that accumulate over time as a result of ineffective microglial control of AD pathology due to lack of Trem218,19.”
From Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease (2020) · cites this paper as [18]
Loss of TREM2 function in Alzheimer's disease mouse models limits microglial plaque surrounding, proliferation, and conversion to disease-associated microglia, leading to more severe neuritic dystrophy.
“loss of TREM2 function in AD mouse models restricts the ability of microglia to surround Aβ plaques15,16, proliferate, and convert to DAM10,15,17, which in turn leads to more profound neuritic dystrophy18,19.”
From Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease (2020) · cites this paper as [18]
Weakening of microglial barriers around amyloid-beta facilitates early spreading and invasiveness of fibrillar amyloid, followed by later amyloid-beta accumulation during disease progression.
“This weakening of microglial barriers around Aβ facilitates spreading and invasiveness of fibrillar amyloid at early stages of disease (130, 131) followed by later accumulation of Aβ during disease progression (114, 132).”
From Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017) · cites this paper as [131]
TREM2-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).”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Yuan et al., 2016
With 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).”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Yuan et al., 2016
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.
“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).”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Yuan et al., 2016
Prior studies show that microglia form a physical barrier around plaques and compact Aβ into dense deposits, protecting against local neurite damage.
“These results are consistent with prior studies showing that microglia form a physical barrier around plaques and compact Aβ into dense deposits, protecting against local neurite damage35–37.”
From Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model (2019) · cites this paper as [37]
Trem2 in plaque-associated microglia promotes plaque compaction and insulation, reducing neuritic toxicity of fibrillary Aβ.
“Trem2 in plaque-associated microglia plays an important role in plaque compaction and insulation to reduce the neuritic toxicity of fibrillary Aβ (Wang et al., 2016; Yuan et al., 2016).”
From Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer’s Disease Models (2018) · cites this paper as Yuan et al., 2016
BAC-TREM2 and Trem2-deficient microglia show dichotomous cellular and molecular phenotypes in AD mouse models, including plaque compaction, microglial process ramification, activated marker expression, and phagocytosis.
“For example, we showed several dichotomous cellular and molecular phenotypes between BAC-TREM2 and Trem2-deficient microglia in mouse models of AD (Jay et al., 2017; Ulrich et al., 2017; Yuan et al., 2016). These include the compaction of amyloid plaques, the ramification of plaque-associated microglial processes, the expression of certain activated microglial markers, and phagocytosis.”
From Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer’s Disease Models (2018) · cites this paper as Yuan et al., 2016
TREM2 is essential for promoting microglial cell association with plaques.
“TREM2 was recently demonstrated to be essential for promoting microglial cell association with plaques44–49.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [49]
Patients with Alzheimer's disease who carry the TREM2R47H mutation show patterns of plaque morphology and neurite dystrophy that resemble the plaques observed in TREM2-deficient amyloid-β depositing mice, indicating that this mutation causes a loss of function.
“Patients with Alzheimer’s disease who carry the TREM2R47H mutation show patterns of plaque morphology and neurite dystrophy that resemble the plaques observed in TREM2-deficient amyloid-β depositing mice49, indicating that this mutation causes a loss of function.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [49]
Plaque-associated microglia contain plaque-derived materials, indicating their capability to phagocytose plaque components.
“plaque-associated microglia have been shown to contain plaque-derived materials27,49, indicating their capability to phagocytose plaque components.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [49]
TREM2 haplodeficiency, ablation, or the TREM2R47H mutation leads to a significant reduction of plaque-associated microglia compared to their TREM2-sufficient counterparts.
“TREM2 haplodeficiency, ablation, or the TREM2R47H mutation that causes a missense variant of TREM2, eads to a significant reduction of plaque-associated microglia compared to their TREM2-sufficient counterparts44–49.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [49]
This plaque-phagocytotic capacity is impaired with TREM2 deficiency.
“This plaque-phagocytotic capacity is impaired with TREM2 deficiency48,49”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [49]
Such morphological changes in plaques are frequently associated with a greater degree of neuritic dystrophy with enlarged, swollen axons and dendrites in close vicinity.
“Such morphological changes in plaques are frequently associated with a greater degree of neuritic dystrophy with enlarged, swollen axons and dendrites in close vicinity48,49”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [49]
TREM2-deficient amyloid-β depositing mice develop significantly enlarged and less compact plaques containing longer and more diffuse star-shaped amyloid fibrils that project from loosely packed cores.
“TREM2-deficient amyloid-β depositing mice develop significantly enlarged and less compact plaques containing longer and more diffuse star-shaped amyloid fibrils that project from loosely packed cores48,49.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [49]
Lack of TREM2 results in impaired plaque trimming, which leads to enlarged plaques with reduced compaction.
“Lack of TREM2 results in impaired plaque trimming, which leads to enlarged plaques with reduced compaction48,49.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [49]
ApoE ablation in APPSwePSEN1dE9 or APPPS1-21 mice results in enlarged plaques with wispy fibre-like structures projecting from loosely packed cores, similar to the plaques observed in TREM2-deficient amyloid-β-depositing mice.
“Interestingly, ApoE ablation in APPSwePSEN1dE9 [G] or APPPS1–21 [G] mice also results in enlarged plaques with wispy fibre-like structures projecting from loosely packed cores120, similar to the plaques observed in TREM2-deficient amyloid-β-depositing mice48,49.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [49]
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“While loss of Trem2 in vitro disrupts Ab phagocytosis by microglia (Kleinberger et al., 2014), Trem2-haplodeficient AD-like mice have shown inconsistent results with respect to the amounts of cerebral Ab deposition (Jay et al., 2015; Ulrich et al., 2014; Wang et al., 2015).”
CD14 and Toll-Like Receptors 2 and 4 Are Required for Fibrillar Aβ-Stimulated Microglial Activation
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Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)
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CD36 Mediates the Innate Host Response to β-Amyloid
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Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts
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TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1
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Coding variants in TREM2 increase risk for Alzheimer's disease
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Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2
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“However, multiple recent lines of evidence indicate that microglia are ineffective at removing fibrillar Ab in vivo (Condello et al., 2011; Liu et al., 2010; Stalder et al., 2001).”
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DAP12-deficient mice fail to develop autoimmunity due to impaired antigen priming.
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TREM2 is upregulated in amyloid plaque-associated microglia in aged APP23 transgenic mice
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CD33 modulates TREM2: convergence of Alzheimer loci
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The nanometer-scale structure of amyloid-Β visualized by atomic force microscopy
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Attenuation of β-Amyloid Deposition and Neurotoxicity by Chemogenetic Modulation of Neural Activity
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Self-citationLight-Induced Dark States of Organic Fluochromes Enable 30 nm Resolution Imaging in Standard Media
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Self-citationMulticolor time-stamp reveals the dynamics and toxicity of amyloid deposition
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Self-citationAmyloid plaque formation precedes dendritic spine loss
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A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease
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Microglia Function in the Central Nervous System During Health and Neurodegeneration
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Self-citationInflammation as a central mechanism in Alzheimer's disease
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Microglia in Alzheimer’s disease
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DAMP-sensing receptors in sterile inflammation and inflammatory diseases
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Role of neuroinflammation in neurodegeneration development
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“Indeed, increased phosphorylated tau and axonal dystrophy have been found around the amyloid plaques in AD patients carrying R47H variant.(201) In line with these results, many studies have suggested that both the total tau and phosphorylated tau are increased in the CSF of R47H carrying AD patients compared with non-…”
ResultTREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease
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Self-citationApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy
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Self-citationMolecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
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TREM2 Is a Receptor for β-Amyloid that Mediates Microglial Function
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The Semantics of Microglia Activation: Neuroinflammation, Homeostasis, and Stress
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TREM2 regulates microglial cholesterol metabolism upon chronic phagocytic challenge
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TREM2 — a key player in microglial biology and Alzheimer disease
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Self-citationInterplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight
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Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy
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Self-citationNew insights into the role of TREM2 in Alzheimer’s disease
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TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways
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Self-citationDisease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer's Disease
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Microglia use TAM receptors to detect and engulf amyloid β plaques
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Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease
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TREM2, microglia, and neurodegenerative diseases
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TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer's Disease
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“Similarly, lack of TREM2 in AD experimental models led to reduced microglia number, clustering and activation around CNS amyloid plaques accompanied by decreased plaque compaction and increased neuritic damage [50, 51, 53].”
BackgroundEmerging diagnostics and therapeutics for Alzheimer disease
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TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury
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TREM2 function impedes tau seeding in neuritic plaques
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Self-citationMicroglia: Agents of the CNS Pro-Inflammatory Response
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Transcriptional signature in microglia associated with Aβ plaque phagocytosis
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Immune Signaling in Neurodegeneration
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Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism
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Self-citationApoE facilitates the microglial response to amyloid plaque pathology
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Self-citationElucidating the Role of TREM2 in Alzheimer’s Disease
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TREM2 Promotes Microglial Survival by Activating Wnt/β-Catenin Pathway
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The identity and function of microglia in neurodegeneration
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Self-citationTrem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology
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Microglia in Alzheimer’s Disease: Activated, Dysfunctional or Degenerative
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Self-citationMouse Models of Alzheimer’s Disease
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Microglial Phagocytosis: A Disease-Associated Process Emerging from Alzheimer’s Disease Genetics
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Autophagy enables microglia to engage amyloid plaques and prevents microglial senescence
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Multiscale causal networks identify VGF as a key regulator of Alzheimer’s disease
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Galectin-3, a rising star in modulating microglia activation under conditions of neurodegeneration
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PLD3 affects axonal spheroids and network defects in Alzheimer’s disease
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- Authors
- Yuan, P., Condello, C., Keene, C. D., Wang, Y., Bird, T. D., Paul, S. M., Luo, W., Colonna, M., Baddeley, D., & Grutzendler, J.
- Affiliations
- Yale University (US)
- University of Washington (US)
- Washington University in St. Louis (US)
- Weill Cornell Medicine (US)
- Corresponding author
- Grutzendler, Jaime
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 90
- Issue
- 4
- Pages
- 724-739
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC4898967
- OpenAlex
- W2408084759
- Cited by
- 817
- References
- 51
- Citations by year
- 2026: 66 · 2025: 75 · 2024: 81 · 2023: 98 · 2022: 92 · 2021: 111 · 2020: 95 · 2019: 61 · 2018: 69 · 2017: 55 · 2016: 12 · 2012: 1
- FWCI
- 35.97
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-10-05)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 CX001006)
- Mayo Clinic
- University of Alberta
- National Institutes of Health (5r01hl106815-06)
- National Institute on Aging (R21AG048181, P30AG019610, P50AG005136)
- National Heart, Lung, and Blood Institute (R01-HL106815)
- National Institute of Neurological Disorders and Stroke (R01NS089662, U24NS072026, R01NS089734)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- TREM2, microglia, Alzheimer's disease, amyloid plaques, axonal dystrophy, tau hyperphosphorylation, DAP12, amyloid fibrils, neuroprotection, AD mouse model
- MeSH terms
- Alzheimer Disease, Amyloid, Animals, Axons, Disease Models, Animal, Humans, Membrane Glycoproteins, Mutation, Receptors, Immunologic, Amyloid beta-Peptides, Neurites, Microglia, Mice, Plaque, Amyloid
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