Deletion of Abi3 gene locus exacerbates neuropathological features of Alzheimer's disease in a mouse model of Aß amyloidosis

Recently, large-scale human genetics studies identified a rare coding variant in the ABI3 gene that is associated with an increased risk of late-onset Alzheimer's disease (AD). However, pathways by which ABI3 contributes to the pathogenesis of AD are unknown. To address this critical question, we determined whether loss of ABI3 function affects pathological features of AD in the 5XFAD mouse model. We demonstrate that the deletion of Abi3 locus significantly increases amyloid-b (Ab) accumulation and decreases microglia clustering around the plaques. Furthermore, long-term potentiation is impaired in 5XFAD;Abi3 knock-out (“Abi3-/-”) mice. Moreover, we identified dramatic changes in the proportion of microglia subpopulations in Abi3-/- mice using a single-cell RNA sequencing approach. Mechanistic studies demonstrate that Abi3 knockdown in microglia impairs migration and phagocytosis. Taken together, our study provides the first in vivo functional evidence that loss of ABI3 function may increase the risk of developing AD by affecting Ab accumulation and neuroinflammation. Overall design: Quant-seq (3' mRNA-seq) analysis of cerebral cortices of female 5xFAD mice with Abi3 +/+ (Abi3 WT) or Abi3 -/- (Abi3 KO) genotypes at 8 months of age