The National Institute on Aging recently awarded $2.16 million to a team of investigators from the University of Tennessee Health Science Center (UTHSC) testing a new way to combat the root cause of neurodegenerative disorders such as Alzheimer's Disease. Francesca-Fang Liao, PhD, professor of Pharmacology, Addiction Science and Toxicology in the College of Medicine, is the NIH contact principal investigator on the project. Wei Li, PhD, distinguished professor in the Department of Pharmaceutical Sciences in the College of Pharmacy, is a multiple principal investigator.

A number of progressive neurodegenerative diseases, such as Alzheimer's, involve the abnormal accumulation of a key protein, tau, in the brain. In healthy neurons, tau binds to and stabilizes internal support structures called microtubules, which help guide nutrients and molecules from the one part of the nerve cell to another. In diseased patients, stressful signals in the brain alter tau, causing it to misfold and detach from microtubules, forming neurofibrillary tangles which are toxic to neurons.

A breakdown in the signaling pathways that can rid cells of misfolded tau and prevent its accumulation is the focus of Dr. Liao's project. Her team is examining new mechamisms that might cause these breakdowns, zeroing in on the link between oxidative stress and the activity of a particular enzymatic molecule, otulin. In previous studies, Dr. Liao has found that inhibiting otulin prevented the accumulation of tau. She hypothesizes that oxidative stress activates otulin, which increases tau aggregation and neurotoxicity. Her project aims to investigate both the mechanisms that regulate tau accumulation, and the mechanisms affected by oxidative stress during otulin-induced tauopathies. It will also test a new otulin-inhibiting drug developed by Dr. Li for its effectiveness in promoting tau clearance and reducing tau's cellular toxicity.

"We are extremely excited to work together as a team to further validate a potential use of this compound in translation," Dr. Liao said.