To view an abstract, select an author from the vertical list on the left.
2017 Grants - Datta
"Leaky" Ryanodine Receptors: Potential Role in Pathogenesis of AD
Dibyadeep Datta, Ph.D.
New Haven, Connecticut
2017 Alzheimer's Association Research Fellowship (AARF)
Why are only certain types of nerve cells in the brain affected in Alzheimer's disease?
Only a specific group of nerve cells in the brain—those involved in higher levels of thinking and memory—are affected by changes characteristic of early Alzheimer's disease, such as the accumulation of protein fragments into tangles that interfere with nerve cell function and cause loss of nerve cells. Nerve cells in these areas of the brain, called the association cortices, appear to be particularly vulnerable to Alzheimer's disease and age-related changes. It remains unclear why these nerve cells are prone to changes that lead to nerve cell loss; one possibility is that these cells are more likely to have increases in calcium signaling. Calcium is highly regulated in neurons, where abnormal levels can cause cellular dysfunction to occur or even cell death.
Dibyadeep Datta, Ph.D., and colleagues propose to examine specific age-related changes in inflammation and abnormal calcium regulation in these specific networks of the association cortices. They hypothesize that inflammation can cause an initial "calcium leak" via specific calcium channels, ryanodine receptor activated channels, releasing calcium from intracellular stores. This in turn drives tau phosphorylation, mitochondrial dysfunction and further inflammatory cascades.
They will study the aging rhesus monkey, which has been shown to develop the same changes in the brain that are seen in individuals with Alzheimer's disease, specifically, accumulation of the protein fragment beta amyloid and tau in the association cortices of the brain, loss of connections between nerve cells, and deficits in thinking and memory. The investigators will compare changes in calcium activation of specific molecules in nerve cells in young and aging monkeys and other animal species. They will also determine whether treatment of aging rats with a drug that has been shown to prevent the calcium leak in heart muscle cells also protects against inflammation, tau accumulation, and nerve cell loss and improves thinking and memory.
This study may reveal whether changes in calcium dysregulation from sub-compartments in the nerve cells in the association cortices makes them particularly vulnerable to degeneration during aging and Alzheimer's disease. It may also provide a novel strategy for protecting the higher brain circuits most vulnerable to degeneration.