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2012 Grants - Hetz
Protective Role of the Transcription Factor XBP1 in Alzheimer's disease
Claudio A. Hetz, Ph.D.
Institute of Biomedical Sciences, University of Chile
2012 New Investigator Research Grant
Beta-amyloid is a key suspect in Alzheimer's disease. This protein fragment is "clipped" from a parent molecule known as amyloid precursor protein (APP). Accumulations of beta-amyloid in the brain have been associated with brain cell damage and death—a process that leads to cognitive and functional decline in Alzheimer's. Recent studies have also found that stress in the nerve cell's endoplasmic reticulum (ER), a part of the cell where proteins are produced, may play a role in amyloid toxicity. This stress appears to be caused by a series of chemical reactions known as the unfolded protein response (UPR).
Claudio A. Hetz, Ph.D., and colleagues have been using mice to study the links between unfolded protein response and Alzheimer's pathologies—such as the brain accumulations of abnormal tau protein and the protein fragment beta-amyloid. They have developed mouse models that either lack or overexpress a protein called X-box binding protein-1 (XBP1), which regulates UPR activities. Preliminary results indicate that the presence of XBP1 helps maintain memory function in the mice. This memory-enhancing property appears to derive from XBP1's ability to control the expression of genes related to memory function. In addition, the researchers found that by reducing XBP1 levels in their mice, they could increase the amount of toxic beta-amyloid in the animals' brains. Further examination showed that XBP1 may control the expression of genes associated with the clipping APP into beta-amyloid.
For this grant, Dr. Hetz and colleagues will conduct a larger study with laboratory cells and mice to confirm their earlier results. They also hope to clarify the mechanisms that underlie XBP1's ability to regulate beta-amyloid production and alleviate memory loss. Ultimately, XBP1 may provide an effective target for Alzheimer's therapies.