Abstract

Aging is the greatest risk factor for developing neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, but it is still not understood why certain cells and regions of the brain are particularly vulnerable to disease. Our research group focuses on lysosomes, which are responsible for degrading and recycling the misfolded proteins that accumulate in these diseases. Lysosomal function declines with age and is disrupted in neurodegenerative disease, suggesting that lysosomal dysfunction may be an important link between normal aging and disease.

Our goal is to understand how lysosomal function changes across different cell types and regions of the aging brain and to identify the molecular pathways that drive these changes. We developed a fluorescent sensor that allows us to measure lysosomal acidity (a key driver of lysosomal function) in the mouse brain and have found that lysosomal acidity changes with age and varies considerably across brain regions. The support provided by Hilblom will allow us to combine this tool with single-cell and spatial transcriptomics to identify genes associated with these differences and determine whether modifying lysosomal pathways can reverse features of brain aging.

Ultimately, we hope to understand how lysosomal dysfunction contributes to the vulnerability of specific brain cells and regions during aging and identify new pathways that could be targeted to prevent or treat age-related neurodegenerative disease.