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2010 Grants - Hetz
Defining the Role of the Unfolded Protein Response in Alzheimer's Disease
Claudio Hetz, Ph.D.
Institute of Biomedical Sciences, University of Chile
2010 New Investigator Research Grant
Brain accumulations of the protein fragment beta-amyloid are thought to disrupt cell-to-cell communication and cause nerve cell death in Alzheimer's disease. But the mechanisms by which amyloid clumps exert their toxicity remain unclear. Recent studies have found that stress in the nerve cell's endoplasmic reticulum, a part of the cell where proteins are produced, may play a role in beta-amyloid toxicity. This stress appears to be caused by a chemical pathway, or series of chemical reactions, known as the unfolded protein response.
Claudio Hetz, Ph.D., and colleagues have been studying links between the unfolded protein response and amyloid toxicity. They have engineered mouse brain cells that lack a protein called x-box binding protein-1 (XBP-1), which promotes the unfolded protein response. Preliminary research has found that these cells can resist the effects of toxic beta-amyloid.
For their proposed grant, Dr. Hetz and colleagues will analyze how XBP-1 makes brain cells vulnerable to amyloid-induced damage. This effort will involve analysis of cultured brain cells and of several animal models engineered to develop Alzheimer-like symptoms. The researchers will also test whether XBP-1 makes Alzheimer-like mice susceptible to cognitive impairments.
The results of Dr. Hetz' study could shed new light on the mechanisms underlying beta-amyloid's role in Alzheimer's. The effort could also lead to new therapies for the disease.