GSE159866
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.