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2016 Grants - Bloom
Tau, mTOR & Neuron Cell Cycle Re-entry: Why Insulin Resistance Promotes Alzheimer’s Disease
George S. Bloom, Ph.D.
University of Virginia
2016 Zenith Fellows Award
How do nerve cells die in Alzheimer’s disease and does insulin help prevent nerve cell death?
Many cells in the body are periodically replaced when other cells divide to form two new cells. In the adult brain, however, most nerve cells (neurons) are unable to divide. So if a nerve cell dies there is nothing to replace it. In Alzheimer’s disease, nerve cells die in much greater numbers than in normal aging, but the cause of this cell loss is not well understood. However, it is thought to involve beta-amyloid, a protein fragment at the center of research into the causes of Alzheimer’s disease.
George S. Bloom, Ph.D., and colleagues have found evidence that small clusters of beta-amyloid, known as oligomers, may signal nerve cells to try to divide. But because the nerve cells are unable to properly complete the process of dividing, they die. The researchers also found evidence that insulin may prevent beta-amyloid from having this effect. Insulin is a hormone that helps the body control blood sugar levels and it also acts in the brain to help nerve cells use sugars as a source of energy.
In diabetes and conditions that precede it, cells become resistant to the effects of insulin. Diabetes and insulin resistance are strong risk factors for Alzheimer’s disease. The studies of Dr. Bloom’s team suggest that insulin resistance may be a factor that contributes to nerve cell death in Alzheimer’s disease.
Dr. Bloom and colleagues have proposed a series of experiments to understand how beta-amyloid triggers nerve cells to try to divide, and how insulin prevents this effect and maintains nerve cell health. They also plan to study another molecule involved in cell division, the protein tau. Tau normally functions as part of the cell structure and helps transport nutrients throughout nerve cells. In Alzheimer’s disease, it is abnormally modified, causing it to form neurofibrillary tangles, one of the characteristic features of the disease.
Researchers have found that abnormal modification of tau can be triggered by beta-amyloid. Dr. Bloom’s team plans to study how modification of tau leads to unsuccessful attempts of nerve cells to divide, ending in cell death. They will also explore how insulin may prevent the modification of tau.
This research will improve our understanding of the causes of nerve cell death in Alzheimer’s disease, and how insulin resistance and diabetes may be involved in this cell loss. The results of these studies could lead to the development of novel treatments to prevent or slow the progression of Alzheimer’s disease.