Microglial CLEC7A restrains amyloid beta plaque pathology in a mouse model of Alzheimer's disease

BACKGROUND: CLEC7A is a surface receptor that is highly upregulated on microglia in many Alzheimer's disease (AD) models. Little is currently known about the role that microglial CLEC7A signaling plays in AD-related pathogenesis. METHODS: We utilized an inducible, central nervous system (CNS) macrophage-specific knockout of Clec7a to evaluate the role of CLEC7A in the 5xFAD mouse model of AD at 5 months of age. We used immunofluorescence microscopy, single nuclei RNA-sequencing, along with biochemical assays to evaluate plaque burden, microglial activity, and neuronal health. RESULTS: CNS macrophage-targeted deletion of CLEC7A in 5xFAD mice led to a two-fold increase in plaque burden, exacerbated neuritic dystrophy, and altered expression of neuronal health genes, but did not appreciably impact microglial activation, plaque engulfment, or disease-associated microglia (DAM) acquisition. DISCUSSION: These findings identify protective roles for CLEC7A in AD-related amyloidosis and suggest that CLEC7A-targeting therapeutics may offer promising strategies to treat AD. Overall design: Comparison of CNS cell types using single-nuclei RNA sequencing of samples derived from brain tissue of 5xFAD (Alzheimer's disease pathology animals) and 5xFAD mice with inducible, conditional loss of Clec7a expression in CNS macrophages.