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2006 Grant - Restituito

Synaptic Functions of Gamma-Secretase

Sophie Restituito, Ph.D.
New York University
New York, New York

2006 New Investigator Research Grant

Gamma-secretase helps to release the beta-amyloid protein fragment, a key suspect in Alzheimer pathology, from a larger protein called the amyloid precursor protein. Some mutations that lead to inherited early-onset Alzheimer's disease have been found to modify gamma-secretase activity, causing increased production of beta-amyloid. This and other findings have contributed to the "amyloid hypothesis," which suggests that overproduction of beta-amyloid is a key step in disease pathology.

But gamma-secretase has many other targets. These include proteins that are found in synapses, specialized junctions through which neurons communicate with each other. These functions have led some scientists to suggest that gamma-secretase may have an important role to play in synaptic activity-a role that could also be related to Alzheimer pathology. In fact, loss of synapses more tightly correlates with the progression of Alzheimer's disease than does the accumulation of beta-amyloid.

Sophie Restituito, Ph.D., and colleagues plan to examine the role of gamma-secretase at the synapse. The researchers will determine of synapses or in synaptic plasticity, a process through which the content of the synapse can change in response to stimulation. Synaptic plasticity is essential for learning and memory.

Restituito will look for gamma-secretase activity in synapses and test whether it is related to changes in the number, composition or localization of receptors. These are "docking sites" for messenger chemicals used in neuron-to-neuron communication. These studies will help determine if gamma-secretase activity is related to synapse loss in Alzheimer's disease.