How genetic mutations lead to neuronal death in Alzheimer's disease

Sheue-Houy Tyan, PhD
The Regents of the University of California (La Jolla, CA)

Co-Principal Investigators

Brock E. Schroeder , PhD
Edward Koo, MD
University of California, San Diego (La Jolla, CA)
Year Awarded:
Grant Duration:
April 1, 2002 to March 31, 2004
Alzheimer's Disease
Award Amount:
Grant Reference ID:
Award Type:
Award Region:
US Southwestern

Effects of Presenilin 1 Mutations on bCatenin Signaling


The death of neurons in the brain is a symptom of Alzheimer's disease (AD) that is believed to be a major factor in the cognitive impairment affecting Alzheimer's patients. The death of neurons may result from the accumulation of plaques between neurons as well as from the formation of neurofibrillary tangles within neurons. However, why these factors are toxic is not known. One theory is that the high-stress environment found in AD can trigger neurons into starting cell division, but the cells lack the appropriate components to divide and, as a consequence, the process results in cell death. Dr. Tyan will focus on the early-onset form of familial AD that is linked to mutations in the presenilin proteins (PS). She proposes that PS1 deficiency and PS1 mutations upregulate b-catenin signaling in the adult brain. This leads to increased levels of the cyclin D1, which is a component used by neurons in their attempt to start dividing in response to environmental challenge. The high levels of cyclin D1 are thought to contribute to abnormal cell division and cell cycle signaling, resulting in the neuronal loss seen in AD. Dr. Tyan is studying transgenic animals to determine whether b-catenin signaling through cyclin D1 and abnormal cell divisions occur in the neurons of animals with AD. Understanding what causes neuronal cell death will help in designing treatments to prevent neuronal death or delay it sufficiently to improve the quality of life for Alzheimer's patients.
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