Grant: Operating Grant: Geroscience Demonstration Grants

Diverse diseases appear during aging and some of the more important ones affect the brain. Specifically, chronological age is the most potent risk factor for the common form of Alzheimer's Disease (AD). This form of AD is not caused by inherited mutations and comprises an enormous challenge for the patients, their families and for public health services. One way to meet this challenge is to test a variety of candidate therapies in animal models but the utility of this approach is thwarted by the availability of suitable models. Inherited forms of AD account for only 10% of cases but are heavily represented in research labs by animal models that overproduce mutant protein molecules involved in the disease. Conversely, models with lower protein production that might better mimic the common form of these diseases are underrepresented. We have created such a "low production" model based on the brain protein called Tau, and, of note, we have observed intriguing animal-to-animal diversity in the disease process. This not only offers a parallel to diversity seen in the human disease but also suggests the action of environmental influences as disease evolves late in the lifespan of these mice. In this work we plan to study how the types of natural bacteria in the gut affect disease, how misshapen forms of Tau protein kill cells and how age-accelerating mutations might affect Tau protein in petri-dish models and in a special area of the mouse brain. As bacterial populations in the gut are more accessible physically and easier to manipulate than protein molecules inside the brain, we believe they comprise a novel and potentially important route towards stopping these brain diseases. intervention.