Functional Analysis of Late-onset Alzheimer’s Disease-Associated Genes in Neurodegeneration and Protein Aggregation-induced Neurotoxicity - Alzheimer’s disease (AD) is the most prevalent form of dementia, selectively impacting specific neuronal subpopulations in distinct brain regions. While extensive research has elucidated the crucial role of abnormally aggregated amyloid beta and tau proteins in AD pathogenesis, the precise etiology remains elusive. Genome- wide association studies have recently identified multiple genetic variants associated with late-onset AD (LOAD), which accounts for 90% of AD cases, indicating a potential genetic predisposition. However, there is still a critical knowledge gap regarding the contribution of these genetic factors to AD pathogenesis, as only a fraction of the identified loci and relevant genes have been investigated for their downstream effects and mechanisms in AD pathology. Our research aims to bridge this knowledge gap and enhance our understanding of the genetic basis of the disease. The objective of this proposed project is to investigate the impact of LOAD-associated genes on neurodegeneration and AD-related neurotoxicity using C. elegans as a tool. In our preliminary studies, we have identified that C. elegans have homologous genes for over half of the identified LOAD-associated genes, and many of these homologs exhibit altered expression levels during normal aging, resembling some observations made in the aging human brain. Indeed, most of the identified human genetic variants are non-coding variants, which can potentially affect expression of target genes. To study neurodegeneration in vivo, we have previously established a system that can recapitulate some aspects of selective neuron vulnerability during aging. Using this system, we observed that individual knockdown of certain C. elegans homologs of LOAD-associated genes during adulthood impacts neurodegeneration patterns in a neuron subpopulation-specific manner, remarkably without affecting organismal lifespan. Building upon these preliminary findings, the proposed study aims to further explore the role of LOAD-associated genes, using our well-characterized neurodegeneration models, in conjunction with the C. elegans AD transgenic models (expressing human amyloid beta and mutant Tau in neurons) previously developed by the research community. We will employ various approaches encompassing genetic, cell biology, biochemistry, and behavioral analysis, to (1) define the contribution of LOAD-associated genes to the selective vulnerability of neurons during aging, and to (2) identify LOAD-associated genes that interact with amyloid beta and Tau aggregation to mediate neurotoxicity. Successful completion of this project will provide crucial insights into the genetic underpinnings of AD-related phenotypes. Ultimately, this knowledge will advance our understanding of how risk genes may interact with other genes, lifestyle, or environmental factors to influence an individual’s susceptibility to AD, aiding the development of personalized preventive and therapeutic strategies.
