Project Summary and Abstract Alzheimer’s disease (AD) is the most common form of dementia diagnosed through the presence of tau tangles and amyloid beta (Aβ) plaques within the brain. Aβ is generated from amyloid precursor protein (APP), an integral membrane protein. APP and Aβ localize to mitochondria and mitochondrial associated membranes (MAMs). MAMs are endoplasmic reticulum (ER)-mitochondria contact sites and are associated with altered function of both the ER and mitochondria. Previous studies have shown that MAM activity directly influences APP processing into Aβ. We hypothesize that localization of APP at mitochondria and MAMs dictates Aβ production. Prior studies indicate APP localization at the mitochondria, ER, and MAMs affects their function, but an overall mechanism is not understood. Mitochondrial and ER dysfunction are observed in AD. Impaired mitochondrial bioenergetics, increased oxidative stress, and altered mitochondrial calcium, cholesterol, and phospholipid metabolism are evident in models of AD. MAMs are known to modulate these functional modalities between mitochondria and ER, and upregulation of MAMs is observed in AD. This upregulation of MAM function is hypothesized to drive APP processing into Aβ and disrupt mitochondrial and ER function. We will test our hypothesis in two aims. We will elucidate the effects of APP localization on Aβ production and evaluate if MAM function influences localization of APP. We will address how APP and Aβ production interact with MAM function. We will also evaluate AD and cell-type specific changes between these relationships. Addressing the relationship between MAMs, APP, and Aβ production will provide novel insights into their roles in AD pathology. This F31 award is designed to further Taylor Strope’s career path by complimenting her current training and developing expertise in new areas. These new areas include genome editing and differentiation of induced pluripotent stem cells (iPSCs), mitochondrial/ER biology, and APP biology. At the University of Kansas Medical Center (KUMC), Taylor Strope will work with her mentors, Drs. Wilkins and Swerdlow of the Alzheimer’s Disease Research Center. The expert mentoring team, strong training environment, and research experience are imperative for advancing Taylor Strope’s academic career goals.