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, such as amyloid-? (A?) accumulation, inflammation, and synaptic dysfunction, in the 5XFAD mouse model. We demonstrate that the deletion of Abi3 locus significantly increases levels of soluble and insoluble A? and amyloid plaques and decreases microglia clustering around the plaques. Furthermore, long-term potentiation is impaired in Abi3 knock-out (Abi3-/-) mice. Nanostring-based transcriptomic analyses indicate that genes involved in microglial phagocytosis and immune response pathways are dysregulated in Abi3-/-mice. Moreover, we identified dramatic changes in microglia subpopulations in Abi3-/- mice using a single-cell RNA sequencing approach. 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 A? pathway and neuroinflammation. Overall design: Two male 9-month old 5XFAD mice and two male 9-month old 5XFAD;Abi3 KO mice were used.