Targeting ATP1B3 to suppress EVs–mediated tau propagation in CBD and PSP

Pathway Grant

Zhengrong Zhang, Mayo Clinic Jacksonville

Neurodegenerative diseases such as corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are caused by the abnormal build-up of a protein called tau, which spreads from cell to cell and damages the brain. Recent research suggests that tau can travel between brain cells inside tiny packages called extracellular vesicles (EVs), acting like vehicles that carry harmful tau to neighboring cells. However, the molecules that control how tau is packaged into these vesicles remain poorly understood. Our preliminary studies identified a protein called ATP1B3 that binds with tau and helps load tau into these vesicles, with particularly elevated levels observed in CBD brains. These suggested it may play a central role in tau spread. In this project, we will study tiny vesicles carrying the protein ATP1B3 from the brains of people with CBD and PSP. We aim to understand how these vesicles contribute to the buildup and spread of tau protein and how they affect the health of brain cells. We will also test whether removing ATP1B3 from human neurons can reduce tau in vesicles, prevent it from spreading to other cells, and protect the health of brain cells. By understanding how ATP1B3 contributes to tau propagation through the EV pathway, we hope to reveal new strategies to slow or stop tau spread in these diseases. This work could lead to innovative therapies that protect brain cells and improve the lives of people living with CBD, PSP, and related disorders.