Project description:We examined the role of TREM2 on microglia responses to amyloid-beta deposition in a mouse model of Alzheimer's disease Microglia were FACS-purified from 8.5 month old WT, Trem2-/-, 5XFAD, and Trem2-/- 5XFAD mice
Project description:TREM2 is a microglial-specific gene implicated in late-onset Alzheimer's Disease (AD). Recent studies have identified that Trem2-deficient mice exhibit transcriptional changes in microglial gene expression that minimize the upregulation of lipid metabolism and lysosomal genes in AD disease models. We find that chronic phagocytic challenge from demyelination generates similiarly attenuated expression of lysosomal and lipid metabolism genes in microglia isolated from Trem2 knockout mouse brain.
Project description:TREM2 is a microglial-specific gene implicated in late-onset Alzheimer's Disease (AD). Recent studies have identified that Trem2-deficient mice exhibit transcriptional changes in microglial gene expression that minimize the upregulation of lipid metabolism and lysosomal genes in AD disease models. We find that chronic phagocytic challenge from demyelination generates similiarly attenuated expression of lysosomal and lipid metabolism genes in microglia isolated from Trem2 knockout mouse brain.
Project description:TREM2 is a microglial-specific gene implicated in late-onset Alzheimer's Disease (AD). Recent studies have identified that Trem2-deficient mice exhibit transcriptional changes in microglial gene expression that minimize the upregulation of lipid metabolism and lysosomal genes in AD disease models. We detect similiarly attenuated expression of lipid metabolism genes in microglia isolated from brains of aged Trem2 knockout mice.
Project description:Microglia are phagocytic cells that survey the brain and perform neuroprotective functions in response to tissue damage, but their activating receptors are largely unknown. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immunoreceptor whose loss-of-function mutations in humans cause presenile dementia, while genetic variants are associated with increased risk of neurodegenerative diseases. In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation and inflammatory responses in vitro. However, it is unknown how TREM2 contributes to microglia function in vivo. Here, we identify a critical role for TREM2 in the activation and function of microglia during cuprizone (CPZ)-induced demyelination. TREM2-deficient (TREM2(-/-)) mice had defective clearance of myelin debris and more axonal pathology, resulting in impaired clinical performances compared to wild-type (WT) mice. TREM2(-/-) microglia proliferated less in areas of demyelination and were less activated, displaying a more resting morphology and decreased expression of the activation markers MHC II and inducible nitric oxide synthase as compared to WT. Mechanistically, gene expression and ultrastructural analysis of microglia suggested a defect in myelin degradation and phagosome processing during CPZ intoxication in TREM2(-/-) microglia. These findings place TREM2 as a key regulator of microglia activation in vivo in response to tissue damage. Two STAGE (6weeks 12 weeks),
Project description:The R47H variant of TREM2 is associated with higher risk of Alzheimer's disease. We generated mice expressing the common variant or R47H variant of human TREM2 in the absence of murine TREM2 on the 5XFAD mouse model of Alzheimer's disease.
Project description:TREM2, a microglia-specific receptor, is strongly associated with Alzheimer’s disease (AD) risk and modulates microglial responses critical to AD pathogenesis. However, its role in tauopathy and neurodegeneration remains unclear. Here, by using a PS19 tauopathy mouse model with inducible overexpression of human wild-type TREM2 (TREM2-WT) or the R47H variant (TREM2-R47H), we show that TREM2-WT overexpression modestly reduces soluble phosphorylated tau (p-tau) levels and mildly preserves neuronal integrity, whereas TREM2-R47H fails to impact p-tau levels or neurodegeneration. Single-cell RNA sequencing revealed that TREM2-WT enhances disease-associated microglia (DAM) signatures, while TREM2-R47H drives the MHCII+ microglial phenotypes. These findings demonstrate that TREM2-WT confers modest benefits in tauopathy models, whereas TREM2-R47H exhibits reduced functionality. Our study underscores the therapeutic potential of enhancing TREM2 activity to modulate microglial responses and mitigate neurodegeneration in AD.
Project description:Transcription profiling by array of microglia purified from wild type and TREM2 deficient microglia in a mouse model of Alzheimer's disease
