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TREM2 Drives Microglia Response to Amyloid-β via SYK-dependent and -independent Paths [DAP12KI scRNA-seq]

ABSTRACT: Genetic studies have highlighted microglia as pivotal in orchestrating Alzheimer’s disease (AD). Microglia that adhere to Aβ plaques acquire a transcriptional signature, “diseaseassociated microglia” (DAM), which largely emanates from the TREM2-DAP12 receptor complex that transmits intracellular signals through the protein tyrosine kinase SYK. The human TREM2R47H variant associated with high AD risk fails to activate microglia via SYK. We found that SYK-deficient microglia cannot encase Aβ plaques, accelerating brain pathology and behavioral deficits. SYK deficiency impaired the PI3K-AKT-GSK3β-mTOR pathway, incapacitating anabolic support required for attaining the DAM profile. However, SYK-deficient microglia proliferated and advanced to an Apoe-expressing prodromal stage of DAM; this pathway relied on the adaptor DAP10, which also binds TREM2. Thus, microglial responses to Aβ involve non-redundant SYK- and DAP10-pathways. Systemic administration of an antibody against CLEC7A, a receptor that directly activates SYK, rescued microglia activation in mice expressing the TREM2R47H allele, unveiling new options for AD immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE210257 | GEO | 2022/10/10

REPOSITORIES: GEO

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TREM2 Drives Microglia Response to Amyloid-β via SYK-dependent and -independent Paths [SYK and TREM2 scRNA-seq]

Project description:Genetic studies have highlighted microglia as pivotal in orchestrating Alzheimer’s disease (AD). Microglia that adhere to Aβ plaques acquire a transcriptional signature, “diseaseassociated microglia” (DAM), which largely emanates from the TREM2-DAP12 receptor complex that transmits intracellular signals through the protein tyrosine kinase SYK. The human TREM2R47H variant associated with high AD risk fails to activate microglia via SYK. We found that SYK-deficient microglia cannot encase Aβ plaques, accelerating brain pathology and behavioral deficits. SYK deficiency impaired the PI3K-AKT-GSK3β-mTOR pathway, incapacitating anabolic support required for attaining the DAM profile. However, SYK-deficient microglia proliferated and advanced to an Apoe-expressing prodromal stage of DAM; this pathway relied on the adaptor DAP10, which also binds TREM2. Thus, microglial responses to Aβ involve non-redundant SYK- and DAP10-pathways. Systemic administration of an antibody against CLEC7A, a receptor that directly activates SYK, rescued microglia activation in mice expressing the TREM2R47H allele, unveiling new options for AD immunotherapy.

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Project description:The most common form of senile dementia, Alzheimer’s disease (AD), is characterized by Aβ plaques and neurofibrillary tangles in the CNS. AD genetic studies have identified high-risk hypomorphic variants in TREM2, a myeloid cell surface receptor that enables concerted microglial responses to Aβ plaques and neuronal cell death, including proliferation, survival, clustering and phagocytosis. How TREM2 promotes these responses is not known. Here, we demonstrate that TREM2 drives mTOR signaling, which maintains high ATP levels, supports biosynthetic pathways and suppresses AMPK phosphorylation and autophagy. In vitro, TREM2-deficient macrophages undergo dramatically increased autophagy and die in response to growth factor limitation or ER stress. Excessive autophagy is also evident in microglia from Trem2-/- 5XFAD mice and in post-mortem specimens from AD patients carrying TREM2 risk variants. Metabolic derailment, autophagy and cell death can be circumvented by engaging alternative energy production pathways. Thus, restoring microglial energetic and anabolic levels may be a future therapeutic avenue for TREM2-associated neurological disease.

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Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and -independent cellular responses in Alzheimer’s disease [7 months]

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Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and -independent cellular responses in Alzheimer’s disease [15 months]

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Transcriptome and proteome profiling reveals TREM2-dependent and -independent glial response and metabolic perturbation in an Alzheimer’s mouse model

Project description:Elucidating the intricate molecular mechanisms of Alzheimer's disease (AD) requires a multidimensional analysis incorporating various omics data. In this study, we employed transcriptome and proteome profiling of AppNL-G-F, a human APP knock-in model of amyloidosis, at the early and mid-stages of amyloid-beta (Aβ) pathology, to delineate the impacts of Aβ deposition on brain cells. By contrasting AppNL-G-F mice with TREM2 (Triggering receptor expressed on myeloid cells 2) knockout models, our study further investigates the role of TREM2, a well-known AD risk gene, in influencing microglial responses to Aβ pathology. Our results highlight microglial activation as a central feature of Aβ pathology, characterized by the significant upregulation of microglia-specific genes related to immune responses such as complement system and antigen presentation, and catabolic pathways such as phagosome formation and lysosome biogenesis. The absence of TREM2 markedly diminishes the induction of these genes, impairs Aβ clearance, and exacerbates dystrophic neurite formation. Importantly, TREM2 is required for the microglial engagement with Aβ plaques and the formation of compact Aβ plaque cores. Furthermore, this study reveals substantial disruptions in energy metabolism and protein synthesis, signaling a shift from anabolism to catabolism in response to Aβ deposition. This metabolic alteration, coupled with a decrease in synaptic protein abundance, occurs independently of TREM2, suggesting the direct effects of Aβ deposition on synaptic integrity and plasticity. In summary, our findings demonstrate significant microglial activation and metabolic disruption following Aβ deposition, offering mechanistic insights into Aβ pathology and highlighting the potential of targeting these pathways in AD therapy.

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