AD-Linked TREM2 Mutation Induces Unique Microglial States Associated with Toxic Function in Tauopathy
68 Pages Posted: 16 Jul 2019 Sneak Peek Status: Review CompleteMore...
The hemizygous R47H variant of TREM2, a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). To understand its pathogenicity, we generated knock-in mice in which mouse Trem2 was replaced with wild-type or R47H human TREM2. One allele of R47H-hTREM2 was sufficient to induce cognitive deficits and alter synaptic transmission. In knock-in mice with tau inclusions, R47H-hTREM2 exacerbated spatial learning and memory deficits only in female mice. Bulk and single-nuclei RNA-sequencing of hippocampal tissue from female tauopathy mice revealed R47H-induced upregulation of cytokine signaling and microglial clusters with unique R47H-associated signatures. Single-nuclei RNA-sequencing of cortex from AD patients with and without R47H-TREM2 established transcriptomic changes in glial populations that correlated significantly with those observed in the R47H tauopathy mouse model. By unraveling disease-enhancing properties of the R47H mutation, our findings provide new directions for developing microglia-targeted AD therapies.
Keywords: TREM2, R47H, microglia, inflammation, tauopathy, single-nuclei RNA-sequencing, Alzheimer's disease, memory impairment, synaptic function
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