Saturday, May 21, 2022
5/21/2022
Project Summary/Abstract 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 effect of the 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 analyze transcriptome and proteome altered by ABI3 knockout and knock-in. In Aim 3, 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.
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