Abstract 2036 The Impact of Heat Stress on R-loop-associated Genomic Stress and Gene Expression Dysregulation in Alzheimer's Disease

Dementia affects over 50 million people worldwide, with Alzheimer's disease (AD) being the most prevalent form characterized by progressive decline in memory and cognitive function along with neuronal cell loss. The rise in AD is closely linked to aging, influencing molecular processes associated with age-related neurodegenerative disease. Abnormal R-loop formation has been implicated in various human diseases, including neurodegenerative disorders. R-loops form primarily during transcription and consist of a DNA-RNA hybrid and misplaced single-strand DNA. The aberrant R-loop formation is linked to dysregulation of gene expression, genomic instability, and increased DNA damage. As neurodegenerative pathologies, such as AD, are mostly sporadic, there is growing recognition of the environment as a key risk factor for disease onset. To explore this, we use Drosophila melanogaster with neuronal overexpression of mutant human Tau as our AD model, simulating environmental risk through heat stress. Here we aim to investigate how elevated environmental temperature correlates with R-loop levels, genomic instability, and gene expression regulation in AD, using DNA and protein immunoassays and quantitative PCR, respectively. Our data indicates that mild heat stress induces changes in global R-loop levels in AD flies compared to controls. This suggests that external factors may be a significant driver of R-loop-associated genomic instability and dysregulation of gene expression observed in AD. These studies will enhance our understanding of molecular pathways associated with age-related neurodegenerative pathologies and may open avenues for innovative therapeutic approaches to delay or prevent the onset of AD and potentially other neurodegenerative diseases. This work is supported by the Ralph W. and Grace M. Showalter Research Trust.