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

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

PROVIDER: PRJNA590042 | ENA |

REPOSITORIES: ENA

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

Project description:Glia have been implicated in Alzheimer’s disease (AD) pathogenesis. Variants of the microglia receptor TREM2 increase AD risk and activation of “disease-associated microglia” (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene expression changes associated with AD pathology and TREM2 in 5XFAD mice and human AD by snRNA-seq. We confirmed the presence of Trem2-dependent DAM and identified a novel Serpina3n+C4b+ reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less palpable in TREM2 R47H and R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.

2019-12-31 | GSE140510 | GEO

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

2019-12-31 | GSE140399 | GEO

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

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

| PRJNA589621 | ENA

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

Project description:Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and -independent cellular responses in Alzheimer’s disease

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Single-nucleus RNA sequencing of dorsolateral prefrontal cortex from normal, pathological aging, and Alzheimer’s disease human brains

Project description:We performed single-nucleus RNA sequencing of the dorsolateral prefrontal cortex from 15 normal, pathological aging, and Alzheimer’s disease human brains that varied by APOE and TREM2 genotype to analyze cell-type specific transcriptomic changes across the range of Alzheimer’s disease pathology and genetic risk factors.

2023-10-02 | GSE243292 | GEO

TREM2 is a global regulator of microglia energetic and biosynthetic metabolism during steady state and in Alzheimer’s disease

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.

2017-08-15 | GSE98563 | GEO

Single-nucleus RNA-seq of aortas from Ldlr-/- and Ldlr-/-Trem2-/- atherosclerotic mice

Project description:Single-nucleus RNA-seq of aortas was performed in Ldlr-/- and Ldlr-/-Trem2-/- mice fed a high fat diet for 10 weeks

2024-01-12 | GSE243086 | GEO

Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease.

Project description:Glia have been implicated in Alzheimer's disease (AD) pathogenesis. Variants of the microglia receptor triggering receptor expressed on myeloid cells 2 (TREM2) increase AD risk, and activation of disease-associated microglia (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene-expression changes associated with AD pathology and TREM2 in 5XFAD mice and in human AD by single-nucleus RNA sequencing. We confirmed the presence of Trem2-dependent DAM and identified a previously undiscovered Serpina3n+C4b+ reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral-nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less evident in TREM2-R47H and TREM2-R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.

| S-EPMC6980793 | biostudies-literature

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.

2022-10-10 | GSE195518 | GEO

Differential Effects of Partial and Complete Loss of TREM2 on Microglial Injury Response and Tauopathy [RNA-Seq]

Project description:Late-onset Alzheimer’s disease is the most common form of dementia. A rare hemizygous variant in a microglial-expressed gene, Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), significantly increases risk for late-onset Alzheimer’s disease. This variant is thought to cause loss of function, inducing TREM2 haploinsufficiency. The ramifications of TREM2 haploinsufficiency on microglial function and tau pathology are major gaps in the field. We find that in contrast to the protective effects of complete TREM2 deficiency, TREM2 haploinsufficiency exacerbates tau pathology, inflammation, and atrophy at a late stage of disease in a mouse model of tauopathy. The differential effects of partial and complete loss of TREM2 are important considerations for TREM2-targeted therapeutic strategies.

2018-09-20 | GSE118628 | GEO

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