In recent large-scale genome-wide analysis studies, a rare coding variant was identified in Abelson interactor
family member 3 (ABI3) gene and this variant is associated with increased risk of late-onset Alzheimer's disease
(LOAD). ABI3 is highly conserved across multiple species, including humans and mice. Interestingly, it is highly
expressed in microglia and relatively more abundant in the hippocampus, compared to the other brain regions.
The overarching goal of this application is to understand the role of ABI3 in microglia function and the
mechanisms by which ABI3 affects the pathogenesis of AD. We propose the following Specific Aims to test our
hypotheses. In Aim 1, we will determine the effect of Abi3 deletion on Alzheimer's disease pathology using two
mouse models. By performing unbiased transcriptomic and proteomic analyses, we will identify the potential key
regulators of Abi3-mediated effects. We will conduct further functional and biochemical experiments to dissect
the mechanism based on these findings. In Aim 2, we will investigate the function of Abi3 in microglia cells to
understand cellular mechanisms by which Abi3 affects the pathogenesis of AD. We will utilize a genome editing
approach to delete ABI3 gene in human microglial cells. In Aim 3, we will determine the effect of ABI3 rare-
coding variant on AD pathology using ABI3 knock-in mouse model. We will perform brain imaging and
electrophysiology experiments to assess the functional effects of ABI3 risk variant. In addition, we will assess
neuropathological phenotypes in the brains. To identify the potential pathways and key regulators, we will
perform transcriptome and proteome analyses. In addition, we will perform microglial cellular assays to determine
the effects of ABI3 risk variant on microglia functions. Furthermore, we will use RNA interference approach to
knock-down the genes of our interest to dissect the mechanism behind the ABI3 risk variant-mediated changes.
The successful completion of this study will provide novel insights into the mechanisms of AD, in particular,
microglial functions mediated by Abi3. Our long-term goal is to identify new druggable targets for the effective
treatment of AD.