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2008 Grants - Wetzel
The Role of Amyloid-Beta Aggregate Polymorphism in Alzheimer's Disease
Ronald Wetzel, Ph.D.
University of Pittsburgh
2008 Investigator-Initiated Research Grant
Beta-amyloid (also call amyloid-beta) is a protein fragment that aggregates to form amyloid plaque, a characteristic feature of Alzheimer pathology. For many years, scientists believed that formation of amyloid plaque was a crucial step in the progression of Alzheimer's disease, since amyloid plaques were known to be toxic to nerve cells. In recent years, however, evidence has accumulated that smaller aggregates of beta-amyloid (oligomers) may be the crucial toxic form.
According to this new concept, amyloid plaque may actually serve a beneficial purpose by removing beta-amyloid from the fluid surrounding nerve cells, thereby reducing the number of toxic beta-amyloid oligomers. Ronald Wetzel, Ph.D., and colleagues have extended this concept further by proposing that amyloid plaques can have different molecular conformations (polymorphisms) and that the precise conformation affects the amount of beta-amyloid that remains free in the brain. If this idea is correct, then the conformation of amyloid plaque that forms may influence the rate at which Alzheimer's disease progresses in different individuals.
Dr. Wetzel and colleagues plan to study how different conformations of amyloid plaque accumulate new beta-amyloid molecules and how that process influences the amount of free beta-amyloid in the brain. They will then use this information to study amyloid plaques in brain material from patients who have died from Alzheimer's disease. The researchers will study how plaque conformation affects the rate of progression and severity of disease. These studies may clarify the factors that influence the risk of Alzheimer's disease, the age of onset of the disease and its rate of progression. They may also identify new molecular targets that can be used for diagnosis and treatment.