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

INTRODUCTION: CLEC7A is a surface receptor that is highly upregulated on microglia in many Alzheimer's disease (AD) models. Little is 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 twofold increase in plaque burden, exacerbated neuritic dystrophy, and altered the expression of neuronal health genes, but did not appreciably impact microglial activation, plaque engulfment, or disease-associated microglia acquisition. DISCUSSION: These findings identify protective roles for CLEC7A in AD-related amyloidosis and suggest that CLEC7A-targeting therapeutics may offer promising strategies for treatment of AD. HIGHLIGHTS: Conditional loss of CLEC7A in central nervous system (CNS) macrophages of 5xFAD mice results in increased amyloid beta deposition. Loss of CLEC7A does not alter the disease-associated microglia transcriptional program or affect the recruitment of microglia to plaque surfaces. Exacerbation of amyloid deposition with loss of CNS-macrophage CLEC7A is associated with worsened neuronal health highlighted by increased neuritic dystrophy.