Project 461952

A healthy brain requires a healthy body. It is increasingly recognized that by improving the general metabolism of the body, one can improve brain function. This may be particularly true for Alzheimer disease (AD). In the last 20 years, we have learned that metabolic diseases such as diabetes and poor life habits increase the risk of developing AD. Fibroblast growth factor-21 (FGF21) is a newly discovered hormone secreted by the liver during fasting. It was shown to play a central role in the regulation of blood sugar levels, insulin sensitivity, body weight and several aging processes. It can also act directly on the brain. In the last years, we have investigated FGF21 in animal models of AD and obtained exciting preliminary data. We observed that not only the mice lost weight after FGF21 injections, but their memory also improved along with reduced brain amyloid, a hallmark of AD. We also found that FGF21 crosses the blood-brain barrier, suggesting it can interact with neurons. Now, we propose an extensive set of experiments to better determine the real potential of FGF21 as a treatment in AD. We will first gather knowledge on the mechanisms by which FGF21 can improve brain function. Then we will test the effect of FGF21 in different models of AD. Finally, we will look at FGF21 in the blood of volunteers with early signs of cognitive impairments. In summary, the results of this proposed project will tell if there is a way to use this hormone FGF21 to prevent or slow the progression of AD.