The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway

Deczkowska, Aleksandra; Weiner, Assaf; Amit, Ido

doi:10.1016/j.cell.2020.05.003

Cited by 339 publications

(354 citation statements)

References 98 publications

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“…Therefore, our findings suggest that the protective P522R variant sensitizes myeloid cells and potentially allows a more effective response upon neurodegeneration. The opposite phenotypes observed in PLCG2 KO iMGs and Plcγ2-P522R KI mice also support the notion to therapeutically stimulate TREM2 functions [6,16,17,43]. Moreover, the mild increase in the microglial functions due to the Plcγ2-P522R variant may instruct us to what extent we may activate microglia within a therapeutically safe window [16,17,41].…”

Section: Resultssupporting

confidence: 58%

The Alzheimer’s disease-associated protective Plcγ2-P522R variant promotes immune functions

Takalo

Wittrahm

Wefers

et al. 2020

Mol Neurodegeneration

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Background Microglia-specific genetic variants are enriched in several neurodegenerative diseases, including Alzheimer’s disease (AD), implicating a central role for alterations of the innate immune system in the disease etiology. A rare coding variant in the PLCG2 gene (rs72824905, p.P522R) expressed in myeloid lineage cells was recently identified and shown to reduce the risk for AD. Methods To assess the role of the protective variant in the context of immune cell functions, we generated a Plcγ2-P522R knock-in (KI) mouse model using CRISPR/Cas9 gene editing. Results Functional analyses of macrophages derived from homozygous KI mice and wild type (WT) littermates revealed that the P522R variant potentiates the primary function of Plcγ2 as a Pip2-metabolizing enzyme. This was associated with improved survival and increased acute inflammatory response of the KI macrophages. Enhanced phagocytosis was observed in mouse BV2 microglia-like cells overexpressing human PLCγ2-P522R, but not in PLCγ2-WT expressing cells. Immunohistochemical analyses did not reveal changes in the number or morphology of microglia in the cortex of Plcγ2-P522R KI mice. However, the brain mRNA signature together with microglia-related PET imaging suggested enhanced microglial functions in Plcγ2-P522R KI mice. Conclusion The AD-associated protective Plcγ2-P522R variant promotes protective functions associated with TREM2 signaling. Our findings provide further support for the idea that pharmacological modulation of microglia via TREM2-PLCγ2 pathway-dependent stimulation may be a novel therapeutic option for the treatment of AD.

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Section: Resultssupporting

confidence: 58%

The Alzheimer’s disease-associated protective Plcγ2-P522R variant promotes immune functions

Takalo

Wittrahm

Wefers

et al. 2020

Mol Neurodegeneration

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“…3 In addition to microglia, the expression of TREM2 is observed in tissue-resident macrophages, such as macrophages in the hair follicle stem cell niche, adipose tissues, and bone (osteoclast). 3 However, it remained largely unknown whether TREM2 was important in myeloid immunosuppression in the TME.…”

mentioning

confidence: 99%

“…Functional redundancy and non-redundancy among these receptors will require further investigation to determine the optimal therapeutic approach to redirect TAMs. Second, given that TREM2 can be released as a soluble form, 3 the biological and clinical significance of soluble TREM2 in the context of cancer might also reveal additional roles of TREM2. Indeed, soluble CD163 (a scavenger receptor expressed on M2-like macrophages) has been studied to predict prognosis or therapeutic responsiveness to ICIs.…”

mentioning

confidence: 99%

TREM2 marks tumor-associated macrophages

Nakamura

Smyth

2020

Sig Transduct Target Ther

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“…Among these risk genes, TREM2 is the strongest immune-specific risk factor identified to date, with the heterozygous R47H point mutation significantly increasing the odds ratio of developing late-onset AD 1,2 . TREM2 is a single transmembrane receptor expressed exclusively in cells of the myeloid lineage, especially microglia 5,6 . Upon ligand engagement, TREM2, together with its adaptor DAP12/TYROBP, recruits SYK and triggers several signaling cascades such as PI3K-AKT and MAPK pathways 7,8 . These TREM2-dependent pathways in turn regulate many microglial functions, including inflammatory cytokine secretion, proliferation, phagocytosis, cell survival through mTOR signaling, and synapse elimination [9][10][11][12][13][14][15][16][17][18][19][20] .…”

Section: Mainmentioning

confidence: 99%

AD-linked R47H-TREM2mutation induces disease-enhancing proinflammatory microglial states in mice and humans

Sayed

Kodama²,

Udeochu

et al. 2020

Preprint

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The hemizygous R47H variant of TREM2, a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). In this study, we identified a subpopulation of microglia with disease-enhancing proinflammatory signatures associated with the R47H mutation in human AD brains and tauopathy mouse brains. Using transcriptomic analysis at the single-nuclei level from AD patients with the R47H or the common variant (CV)-TREM2 with matched sex, pathology and APOE status, we found that the R47H mutation was associated with cell type- and sex-specific transcriptional changes in human AD brains, with microglia exhibiting the most robust alterations. Further characterization revealed that R47H-associated microglial subpopulations had enhanced inflammatory signatures including hyperactivation of Akt, one of the signaling pathways downstream of TREM2. In a newly-generated tauopathy knock-in mouse model expressing one allele of human TREM2 (hTREM2) with either the R47H mutation or CV, R47H induced and exacerbated tau-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had significant overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of Syk-Akt-signaling, and elevation of a subset of disease-associated microglial signatures. Strikingly, pharmacological Akt inhibition largely reversed the enhanced inflammatory signatures induced by R47H in primary microglia treated with tau fibrils. By unraveling the disease-enhancing properties of the R47H mutation in mouse and human, our findings shed light on an immune-linked AD subtype and provide new directions for modulating microglial immune responses to treat AD.

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The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway

Cited by 339 publications

References 98 publications

The Alzheimer’s disease-associated protective Plcγ2-P522R variant promotes immune functions

The Alzheimer’s disease-associated protective Plcγ2-P522R variant promotes immune functions

TREM2 marks tumor-associated macrophages

AD-linked R47H-TREM2mutation induces disease-enhancing proinflammatory microglial states in mice and humans

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