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2011 Grants - Nakamura
Role of S-Nitrosylation in Alzheimer's Disease
Tomohiro Nakamura, Ph.D.
Sanford-Burnham Medical Research Institute
La Jolla, California
2011 New Investigator Research Grant
Nitric oxide is a type of neurotransmitter, or chemical messenger, that normally helps maintain healthy cell-to-cell communication in the brain. But in Alzheimer's disease and other brain disorders, nitric oxide levels may become abnormally high and cause damage to brain cells. Recent studies have found that this damage may occur because toxic nitric oxide can modify key brain proteins in a way that prevents them from carrying out their normal functions. Such modification is known as S-nitrosylation.
In preliminary studies with Alzheimer's-like animals, Tomohiro Nakamura, Ph.D., and colleagues have found that certain clumps of the protein fragment beta-amyloid, a key suspect in Alzheimer's disease, can induce excessive production of nitric oxide in the brain. This production, in turn, damages brain cell structures called mitochondria and hinders the function of synapses—the tiny channels through which brain cells communicate. Synaptic losses can lead to cognitive decline in dementia. In related research with cultured cells and autopsied human brain tissue, the researchers also found that toxic nitric oxide can disrupt a process called ubiquitination. This process involves the orderly destruction of unwanted proteins in the brain, including beta-amyloid.
For this grant, Dr. Nakamura and colleagues will test the hypothesis that nitric oxide helps promote the toxic activities of beta-amyloid through hindering normal ubiquitination. Specifically, they will determine whether the activities of a protein involved in ubiquitination become altered by nitric acid within cultured cells exposed to beta-amyloid. This research could reveal new information about how Alzheimer's disease develops at its earliest stages and. lead to novel therapies and preventative strategies for the disease.