R01AG071281

The Role of ABI3 in Alzheimer's Disease - 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 an 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 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.

Aim 1: 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. Further functional and biochemical experiments will be conducted to dissect the mechanism based on these findings.

Aim 2: 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 the ABI3 gene in human microglial cells.

Aim 3: Determine the effect of ABI3 rare coding variant on AD pathology using an ABI3 knock-in mouse model. Brain imaging and electrophysiology experiments will be performed to assess the functional effects of the ABI3 risk variant. Additionally, we will assess neuropathological phenotypes in the brains. Transcriptome and proteome analyses will be conducted to identify potential pathways and key regulators. Microglial cellular assays will also be performed to determine the effects of the 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, particularly microglial functions mediated by ABI3. Our long-term goal is to identify new druggable targets for the effective treatment of AD.

Trustees Of Indiana University

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Indianapolis, Indiana 462022266 United States

Single Zip Code

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-19-070)

Amendment Since initial award the total obligations have increased 401% from $731,915 to $3,667,316.