PROJECT SUMMARY Bone morphogenetic proteins (BMP) regulate numerous cell fate decisions during development. Post development there is little expression in most tissues. BMP signaling is reactivated in several age-related diseases including cancer and Alzheimer’s disease (AD). BMP expression in the brain increases with natural aging and is accelerated in AD. BMP drives stem cells in the brain to develop into unwanted astroglial cells and prevents their development into neurons that are required for memory and cognition. Studies in mice show that inhibiting the BMP pathway promotes the development of new neurons and improves cognition. Thanks to our parent R01, we are developing BMPR2 inhibitors for the treatment of lung cancer. With the support of prior Alzheimer’s supplement, we found in both C elegans and lung cancer cells that BMP suppresses AMP activated kinase (AMPK), the master regulator of catabolic metabolism. AMPK promotes mitochondrial viability and activity thus promoting survival. However, hyperactivation of AMPK can cause cell death in neurons and cancer cells. Our BMP inhibitors increase AMPK activity in lung cancer cells. Ym155 inhibits the function of mitochondria and activates AMPK. We discovered that Ym155 combined with BMP inhibitors results in synergistic cell death, AMPK hyperactivation, and increase mitochondrial calcium levels. Also with support of AD supplement grant, initial studies show that treating 42-week C57BL/6 mice with the BMPR2 inhibitor for 4 days increased proliferating cells in the brain. These preliminary studies suggest that BMPR2 inhibition promotes the production of new neurons in old mice. Additional studies are needed with increased exposure to our inhibitors to prove that new neurons are induced. We will perform our next studies in 3xTG-AD mice as they represent a more relevant model of human AD. BMP signaling also decreases the differentiation of precursor cells into oligodendrocytes that produce myelin. Myelin loss occurs early in AD leading to a decline in cognition. We hypothesize BMP inhibition will also prevent the loss of myelin in AD. We will test the hypothesize, in lung cancer cells and C elegans, that hyperactivation of AMPK induced by BMPR2 inhibition and Ym155 induces cell death by Ca++ mediated channels. We will also test the hypotheses in 3xTG-AD mouse model that pharmaceutical inhibition of BMPR2 induces the production of new neurons and/or prevents the loss of myelin. We have established a team of scientists with expertise in BMP biology, C elegans, neuroscience, medicinal chemistry, computational biology, and neural pathology to develop BMP inhibitors for potential use in cancer and/or AD and test our hypotheses. Aim 1. Determine the effects of BMPR2 inhibition on mitochondrial bioenergetics and elaborate the mechanism by which, AMPK hyperactivation promotes mitochondrial Ca++ overload and cell death in lung cancer cell lines and C elegans. Aim 2: Determine in 3xTG-AD mice if pharmac...