2010 Grants - Oddo

The Role of Chaperone-Mediated Autophagy in Alzheimer's Disease

Salvatore Oddo, Ph.D.
University of Texas Health Science Center
San Antonio, Texas

2010 New Investigator Research Grant

Alzheimer's disease is characterized by protein clumps in the brain called amyloid plaques, which contain the protein fragment beta-amyloid, and neurofibrillary tangles, which contain abnormal tau protein. Research suggests that these clumps occur because the production of beta-amyloid and abnormal tau outstrip the brain's ability to clear these molecules.

In preliminary studies with mice engineered to develop Alzheimer-like symptoms, Salvatore Oddo, Ph.D., and colleagues found that the animals showed reduced chaperone-mediated autophagy (CMA). This natural process involves the orderly degradation of unwanted molecules in the body—including beta-amyloid and tau. The researchers then found that inhibited CMA activity in cultured brain cells increased cellular beta-amyloid and tau levels. Based on these results, Dr. Oddo's team hypothesizes that amyloid accumulation in the brain impairs CMA activity. Such impairment, in turn, leads to the build-up of tau, the further build-up of beta-amyloid and eventual cognitive decline.

The investigators plan to test this hypothesis in their proposed study. First, they will use cultured cells to determine how increased beta-amyloid may lead to impaired CMA activity. Second, they will use Alzheimer-like mice to determine how amyloid-induced CMA impairment leads to further protein aggregation and cognitive decline.

Results of this effort could help clarify the mechanisms underlying tau and beta-amyloid development in Alzheimer's disease. They could also suggest new targets for potential Alzheimer treatments.