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2007 Grant - Shen
Mechanisms of Neurodegeneration Caused by Loss of Presenilin Function
Jie Shen, Ph.D.
Brigham and Women's Hospital
2007 Investigator-Initiated Research Grant
Three genes are known to cause rare inherited forms of Alzheimer's disease. Two of these genes provide the genetic "blueprint" for the production of proteins called presenilins. The mutations in these genes somehow change the function of presenilins, but the role of these abnormal proteins in neurodegen-eration is not well understood.
Jie Shen, Ph.D., and colleagues have developed a mouse in which presenilins lose function after birth only in certain regions of the brain. As the mice age, they experience progressive degeneration of brain cells and memory loss.
In this investigation, Dr. Shen's group will assess the mechanism by which
a loss of presenilin function results in neurodegeneration. Using a number
of laboratory tools, they will determine whether the degeneration occurs
(1) because the loss of presenilin function triggers apoptosis, an orderly "self-destruct" mechanism programmed into each cell, or (2) because the loss of function results in necrosis, a disorderly cell death caused by injury to the cell.
The researchers will also explore cell functions and molecular factors that protect brain cells. They hope to determine if loss of presenilin function results in a disruption of these protective mechanisms.
The outcome of this work may elucidate the role of presenilins in normal brain health and disease and may suggest new targets for therapeutic interventions.