Grant: Project Grant

Alzheimer's disease (AD) is the most common form of dementia and a huge burden on health care globally. Despite worldwide efforts, all clinical trials on AD to date have failed. These disappointing findings demonstrate that our understanding of the molecular mechanisms of AD is far from complete, and that novel and effective treatments for AD are urgently needed. It is thought that the accumulation of amyloid-ß (Aß) in the brain is a primary driver of AD. However, an unresolved question is what causes the accumulation of Aß. An increasing body of evidence indicates that alterations in intracellular Ca handling occur in AD long before the appearance of Aß plaques. We recently discovered that genetically suppressing the activity of ryanodine receptor type 2 (RyR2) dramatically reduces Aß level and blocks memory impairment in a mouse model of AD. This exciting finding indicates that RyR2 plays a major role in AD pathogenesis. The goals of this project are to determine RyR2's contributions to AD pathogenesis and to develop novel RyR2-targeted treatments for AD. To achieve these goals, we will determine the role of RyR2 in Aß accumulation, neuron loss, and memory impairment in AD mice. We will define how genetically suppressing or enhancing RyR2 activity affects Ca regulation in AD neurons. Further, we will establish if pharmacological RyR2 inhibition suppresses AD pathology. We have developed the necessary tools and obtained key preliminary data demonstrating the feasibility of our approaches. We expect to reveal for the first time direct evidence that RyR2 plays a major role in AD pathology. We also expect to reveal novel insights into the molecular mechanism underlying abnormal Ca regulation in AD and identify the first RyR2-targeted potential treatment for AD. These proposed studies will advance health-related knowledge and improve health outcomes by uncovering novel fundamental mechanisms and developing novel treatments for AD.