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

Abstract 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.