PROJECT SUMMARY This proposal is motivated by the scarcity of studies and approaches that directly investigate the mechanisms underlying aging and neurodegeneration in the context of physiologically aged neurons. This gap in our knowledge is significant because neurodegeneration is an age-related condition. This long-term goal of this work is to understand the mechanisms responsible for degeneration of the hypothalamus, a key region involved in neuroendocrine regulation. The objective of this proposal is to use cellular reprogramming methods to establish a new platform to investigate the mechanisms of degeneration of a particular hypothalamic neuronal subtype: POMC neurons. POMC neurons are a rare cell type in the brain with a critical neuroendocrine function. The hypothesis is that directly reprogrammed iPOMCs from aged animals and models of Alzheimer's disease will provide a useful system to uncover the mechanisms of POMC aging and degeneration. This hypothesis is supported by strong preliminary data and will be tested through two specific aims: 1) Establish and optimize an in vitro system to study how POMC neurons age and 2) Generate iPOMC cells with mutations associated with familial AD. The first aim will characterize the age-associated phenotypes in iPOMC cells in the context of physiological aging. The second aim will, for the first time, establish a system to study a particular hypothalamic cell type in the context of Alzheimer's Disease. This system is a highly innovative approach to studying rare but critical cell types in the context of aging and neurodegeneration. Moreover, it can be expanded in future studies to generate other hypothalamic cell types, perform mechanistic studies, and implement small molecule screens to study and treat neuroendocrine dysfunction. This work is significant because it will provide a system to study the mechanisms responsible for aging of particular hypothalamic neuronal subtypes, which currently is not feasible with available tools. Ultimately, this approach has the potential to transform our understanding of neurodegenerative disease and lead to new therapies to prevent and treat these conditions.