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2019 Alzheimer's Association Research Grant (AARG)

Vulnerability of rejuvenated synapses in Alzheimer’s Disease

How is nerve cell communication impacted in Alzheimer’s disease?
 

Oliver Schlueter, M.D., Ph.D.
University of Pittsburgh
Pittsburgh, PA - United States



Background

Alzheimer’s is characterized in part by the accumulation of protein fragment beta-amyloid in the brain. These molecules tend to form clumps called amyloid plaques, a hallmark of Alzheimer’s. Beta-amyloid is produced by breaking down a larger protein called beta-amyloid precursor protein (APP). APP breakdown produces beta-amyloid along with several other protein fragments. Each of these protein fragments has a different effect on nerve cells in the brain, not all which appear to be harmful. However, it is difficult to know the effect of each fragment, since all of the fragments are present in the brain at the same time.
 
Dr. Oliver Schlueter proposes that certain APP fragments are important for stimulating the growth of special structures called synapses— that nerve cells use to communicate with each other—in the developing brain early in life. Dr. Schlueter also proposes that in older brains, these same APP fragments refresh existing synapses (called rejuvenation of synapses), that may be vulnerable to the effects of accumulating beta-amyloid, thus impacting nerve cell communication. Dr. Schlueter suggests that stabilizing these refreshed synapses may protect them against disease-related brain changes including beta-amyloid plaques.
 

Research Plan

Dr. Schlueter and colleagues will use genetically engineered mice that do not produce any APP (and so do not produce any beta-amyloid or other APP fragments). To mimic what occurs in the brain of people with Alzheimer’s disease, the researchers will then introduce beta-amyloid in the brain using a novel method developed in their lab. Dr. Schlueter will then use the same method to introduce each type of APP fragment into the brain one at a time to determine which fragment makes the synapses in the brain more susceptible to the effects of accumulating APP and the various fragments.
 

Impact

The study results will help understand the biological mechanisms by which nerve cell communication becomes damaged in Alzheimer’s disease.
 

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