Understanding the Role of Lysosome in Brain Function and Alzheimer’s Disease

Accumulation of tau aggregates in Alzheimer’s disease patient brains influences brain health and cognition. These aggregates are degraded by an intracellular organelle called the lysosome. TFEB plays a critical role in regulating lysosomal function and its clearance ability. Our proposal investigates how TFEB works with the goal to identify ways to harness the lysosomal function to promote brain health and combat age-associated neurodegenerative diseases.

The accumulation of neurofibrillary tangles (NFTs) in a pathological hallmark of Alzheimer’s disease (AD). NFTs are composed of misfolded and aggregated tau protein. They are not only toxic to the neurons, but also activate glial cells in the brain to cause neuroinflammation. NFTs are normally cleared by the lysosome so an efficient lysosome is important in the clearance of the tangles. Our goal is to obtain knowledge about how lysosome regulate Tau pathology and immune function. We are focusing on a specific lysosome-to-nucleus signaling pathway that has never been investigated and using a novel mouse model that disrupts this pathway to address these questions. We have crossed this novel mouse model with a tau mouse model so that we could investigate its contribution to tau pathology. Our first aim is to determine the impact of this lysosome-to-nucleus signaling pathway in lysosomal homeostasis and tau pathology in the neurons. Our second aim is to determine how this lysosome-to-nucleus signaling pathway regulates glia and immune function in response to tau and NFT pathology. We hope that completion of the proposed studies will establish the role of this lysosome-to-nucleus signaling pathway in both neurons and glia. Our work holds promise for developing therapies that augment lysosomal degradative capacities for enhanced NFT clearance as well as managing neuroinflammatory response.