Grant: Project Grant

Clinical trials for Alzheimer's disease (AD) have thus far not succeeded, highlighting an urgent need to better understand how this disease develops. Over the past 5 years, our research program has been focused on identifying the missing links that determine AD progression. In a recently published discovery that received extensive international media attention, we reported that the post-mortem brains of Alzheimer patients exhibit a striking accumulation of triglycerides (stores of fatty acids) on the brain's internal ventricular surface. Using a mouse model of AD, where brains can be analyzed during disease progression, we found that these triglyceride accumulations developed before defects in learning and memory, that they are produced by the AD brain itself, and that one of their consequences is suppression of the brain's stem cell systems. Since brain stem cells participate in functions such as learning, memory, emotion, and general brain maintenance, disruption of brain stem cell activity represents a previously unsuspected mechanism contributing to cognitive deficits in Alzheimer's. This project investigates the therapeutic potential of correcting defects in how the AD brain processes triglycerides. We will use an array of novel animal-based experiments to gain insight into why these triglyceride accumulations happen, whether these accumulations are modifiable by lifestyle factors such as diet and exercise, and whether preventing their occurrence is beneficial in Alzheimer's. Answering these questions may reveal new treatment strategies for this devastating disease.