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2010 Grants - Shen
Role of APP Family in the Synapse
Jie Shen, Ph.D.
Brigham and Women's Hospital
2010 Zenith Fellows Award
Synapses are specialized regions of nerve cells that allow the cells to send rapid signals to one another. They account for many of the specialized abilities of the nervous system, such as the ability to rapidly respond to painful stimuli, as well as some aspects of learning and memory. The function of synapses is known to be impaired in persons with Alzheimer's disease, and this impairment may explain much of the cognitive decline in such persons.
At the center of research into the molecular mechanisms of Alzheimer's disease is the protein APP (amyloid precursor protein). When cut into pieces, APP is the source of beta-amyloid, a fragment of APP that accumulates into amyloid plaques, one of the hallmark features of Alzheimer pathology. However, APP is also believed to have other important functions at synapses, although those functions are not well understood.
Jie Shen, Ph.D. and colleagues are studying the functions of APP in brain cells and synapses. A standard approach for such studies is to use genetic mechanisms to block the expression of APP at birth in animal models. However, animals cannot survive when this is done. Dr. Shen and colleagues have developed a method by which the expression of APP can be turned on or off at selected times and in selected nerve cells. They propose to use this method to study the normal functions of APP in living animals.
Dr. Shen's team will turn off the expression of APP in different parts of the mouse brain and measure how that affects the mouse's ability to perform cognitive tasks and to remember learned tasks. They will also examine how APP expression affects neurodegeneration as well as the function of specific synapses in parts of the brain important for learning and memory. These studies will advance our understanding of the function of APP in the brain, and how that function is altered in Alzheimer's disease.