To view an abstract, select an author from the vertical list on the left.
2012 Grants - Dickstein
Assessing the Effect of Oligomeric Abeta on Neuronal and Synaptic Integrity
Dara Dickstein, Ph.D.
Mount Sinai School of Medicine
New York, New York
2012 New Investigator Research Grant
The protein fragment beta-amyloid is a key suspect in Alzheimer's disease. This fragment tends to accumulate into long chains called fibrils, which in turn lead to the larger clumps (or plaques) that are a hallmark of Alzheimer's. However, current research suggests that beta-amyloid is most toxic during the earliest stages of accumulation, when it forms small clusters called oligomers. These oligomers have been shown to damage the brain's synapses, or the tiny channels through which brain cells communicate with one another. Such synaptic damage leads to dementia-related cognitive decline. However, the exact mechanisms by which oligomers exert their toxicity are unknown. This lack of knowledge is due, in part, to the nature of studying oligomer activity in Alzheimer's-like mice. These engineered animals tend to possess both oligomers and fibrils at the same time—making it difficult to sort out the toxic properties of oligomers from those of fibrils.
Dara Dickstein, Ph.D., and colleagues have developed a research plan that may enable them to overcome the traditional problems of amyloid oligomer studies. They will use mice engineered to express a particular form of inherited Alzheimer's disease. This form involves a variant of amyloid precursor protein—the "parent molecule" of beta-amyloid—called the Dutch mutation. Mice with this mutation produce amyloid oligomers but do not develop fibrils. The researchers will conduct several comparison studies with these mice and with animals that develop both oligomers and fibrils. Specifically, they will compare how beta-amyloid in the different animal models may cause synaptic damage and brain cell death. Dr. Dickstein's team hopes to pinpoint the exact role of oligomers in Alzheimer's pathology. Such results could lead to more precise dementia therapies.