Decoding endolysosomal networks for optimized Aβ1-42 degradation
Alzheimer’s Disease (AD) and Alzheimer’s Disease Related Dementias (ADRD) affect approximately one in nine Americans aged 65 and older. Endolysosomal defects are increasingly recognized to be primary drivers of AD/ADRD pathology. However, the precise relationship between the endolysosomal system and other well-established AD/ADRD hallmarks remains unclear. We will leverage our expertise in functional genomics, membrane trafficking, and single-cell reporters to develop a new genetic toolkit to decode the genetic basis of endosomal trafficking as a central mechanism in AD. First, we will profile the effects of Aß1-42 on endolysosomal trafficking. Second, we will employ advanced genomic tools to comprehensively map how microglia clear Aß, identifying key pathways that can be targeted to boost this clearance. Ultimately, we look to test whether the endolysosomal system can be manipulated to overcome the challenges posed by toxic β-amyloid clusters. Overall, this study advances the hypothesis that the endolysosomal system plays a central role in AD/ADRD pathophysiology, offering mechanistic insights and potential therapeutic strategies.