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Transcriptomic and functional deficits in human TREM2-/- microglia impair response to Alzheimer's pathology in vivo

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE158470 | GEO | 2020/09/24

REPOSITORIES: GEO

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Transcriptomic and functional deficits in human TREM2-/- microglia impair response to Alzheimer's pathology in vivo [scRNA-seq]

Project description:scRNA-sequencing of human xenotransplanted microglia isogenic for TREM2 after exposure to amyloid pathology

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Transcriptomic and functional deficits in human TREM2-/- microglia impair response to Alzheimer's pathology in vivo [bulk RNA-seq]

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Transcriptomic and functional deficits in human TREM2-/- microglia impair response to Alzheimer’s pathology in vivo [RNA-seq]

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Transcriptomic and functional deficits in human TREM2-/- microglia impair response to Alzheimer's pathology in vivo

Project description:Transcriptomic and functional deficits in human TREM2-/- microglia impair response to Alzheimer's pathology in vivo

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Transcriptomic and functional deficits in human TREM2-/- microglia impair response to Alzheimer's pathology in vivo [scRNA-seq]

Project description:Transcriptomic and functional deficits in human TREM2-/- microglia impair response to Alzheimer's pathology in vivo [scRNA-seq]

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Transcriptomic and functional deficits in human TREM2-/- microglia impair response to Alzheimer's pathology in vivo [bulk RNA-seq]

Project description:Transcriptomic and functional deficits in human TREM2-/- microglia impair response to Alzheimer's pathology in vivo [bulk RNA-seq]

| PRJNA665286 | ENA

Transcriptomic and functional deficits in human TREM2-/- microglia impair response to Alzheimer’s pathology in vivo [RNA-seq]

Project description:Transcriptomic and functional deficits in human TREM2-/- microglia impair response to Alzheimer’s pathology in vivo [RNA-seq]

| PRJNA662330 | ENA

Gene expression and functional deficits underlie TREM2-knockout microglia responses in human models of Alzheimer's disease.

Project description:The discovery of TREM2 as a myeloid-specific Alzheimer's disease (AD) risk gene has accelerated research into the role of microglia in AD. While TREM2 mouse models have provided critical insight, the normal and disease-associated functions of TREM2 in human microglia remain unclear. To examine this question, we profile microglia differentiated from isogenic, CRISPR-modified TREM2-knockout induced pluripotent stem cell (iPSC) lines. By combining transcriptomic and functional analyses with a chimeric AD mouse model, we find that TREM2 deletion reduces microglial survival, impairs phagocytosis of key substrates including APOE, and inhibits SDF-1α/CXCR4-mediated chemotaxis, culminating in an impaired response to beta-amyloid plaques in vivo. Single-cell sequencing of xenotransplanted human microglia further highlights a loss of disease-associated microglial (DAM) responses in human TREM2 knockout microglia that we validate by flow cytometry and immunohistochemistry. Taken together, these studies reveal both conserved and novel aspects of human TREM2 biology that likely play critical roles in the development and progression of AD.

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Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer's disease model.

Project description:TREM2 is a receptor for lipids expressed in microglia. The R47H variant of human TREM2 impairs ligand binding and increases Alzheimer's disease (AD) risk. In mouse models of amyloid ? (A?) accumulation, defective TREM2 function affects microglial response to A? plaques, exacerbating tissue damage, whereas TREM2 overexpression attenuates pathology. Thus, AD may benefit from TREM2 activation. Here, we examined the impact of an anti-human TREM2 agonistic mAb, AL002c, in a mouse AD model expressing either the common variant (CV) or the R47H variant of TREM2. Single-cell RNA-seq of microglia after acute systemic administration of AL002c showed induction of proliferation in both CV- and R47H-transgenic mice. Prolonged administration of AL002c reduced filamentous plaques and neurite dystrophy, impacted behavior, and tempered microglial inflammatory response. We further showed that a variant of AL002c is safe and well tolerated in a first-in-human phase I clinical trial and engages TREM2 based on cerebrospinal fluid biomarkers. We conclude that AL002 is a promising candidate for AD therapy.

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Functional BRI2-TREM2 interactions in microglia: implications for Alzheimer's and related dementias

Project description:ITM2B/BRI2 mutations cause Alzheimer's Disease (AD)-related dementias. We observe heightened ITM2B/BRI2 expression in microglia, a pivotal cell type in AD due to risk-increasing variants in the microglial gene TREM2. Single-cell RNA-sequencing demonstrates a Trem2/Bri2-dependent microglia cluster, underscoring their functional interaction. α-secretase cleaves TREM2 into TREM2-CTF and sTREM2. As BRI2 hinders α-secretase cleavage of the AD-related Aβ-Precursor-Protein, we probed whether BRI2 influences TREM2 processing. Our findings indicate a BRI2-TREM2 interaction that inhibits TREM2 processing in heterologous cells. Recombinant BRI2 and TREM2 proteins demonstrate a direct, cell-free BRI2-TREM2 ectodomain interaction. Constitutive and microglial-specific Itm2b-Knock-out mice, and Itm2b-Knock-out primary microglia provide evidence that Bri2 reduces Trem2 processing, boosts Trem2 mRNA expression, and influences Trem2 protein levels through α-secretase-independent pathways, revealing a multifaceted BRI2-TREM2 functional interaction. Moreover, a mutant ITM2B dementia mouse model exhibits elevated Trem2-CTF and sTrem2, mirroring sTREM2 increases in AD patients. Lastly, Bri2 deletion reduces phagocytosis similarly to a pathogenic TREM2 variant that enhances processing. Given BRI2's role in regulating Aβ-Precursor-Protein and TREM2 functions, it holds promise as a therapeutic target for AD and related dementias.

| S-SCDT-10_1038-S44319-024-00077-X | biostudies-other

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