Grant: Project Grant

Alzheimer's disease (AD) is the most common form of dementia and a huge burden on health care globally. It is widely thought that the accumulation of amyloid-beta (A-beta) in the brain is a primary driver of AD. Over the past decades, AD research has largely targeted the amyloid cascade to reduce A-beta depositions. Unfortunately, current A-beta-targeted treatments only slowed, but did not stop the cognitive decline of AD patients. These disappointing findings indicate that our understanding of the mechanisms of AD is far from complete, and that novel and effective treatments for AD are urgently needed. We have recently discovered that genetically increasing the activity of ryanodine receptor 2 (RyR2) induces and exacerbates AD-related neuronal dysfunctions. On the other hand, genetically and pharmacologically reducing RyR2 activity prevents and reverses AD-related deficits. These findings suggest that RyR2 plays a critical role in AD pathogenesis and represents a promising therapeutic target for AD. The overall goal of this project is to define the role of RyR2 in learning and memory and in the pathogenesis of AD. To achieve this goal, we will determine how RyR2 function is involved in learning and memory, and how RyR2 dysfunction contributes to the pathogenesis of AD. To develop novel RyR2-targeted treatments for AD, we will assess whether inhibition of RyR2 activity suppresses AD pathology. We have developed unique research tools that are necessary for the proposed studies and obtained key preliminary data demonstrating the feasibility of our approaches. We expect to reveal novel insights into the mechanisms underlying the role of RyR2 in memory formation and the pathogenesis of AD, and identify potential novel treatments for AD. These proposed studies will advance health-related knowledge and improve health outcomes by uncovering novel mechanisms and developing novel treatments for AD.