PROJECT SUMMARY / ABSTRACT Alzheimer’s Disease is a debilitating degenerative disease without effective treatment that is increasing in prevalence. Developing effective therapies has been impeded because the underlying biological mechanisms driving disease pathogenesis are still poorly understood. Abnormal cleavage of amyloid precursor protein (APP) that generates aggregating forms of neurotoxic amyloid-beta (Aβ) protein has been a focus of investigation for many years. Although very rare forms of early onset familial AD caused by mutations in APP or processing-associated proteins PSEN1 and PSEN2 substantiate a role for Aβ in the pathogenesis of AD, most cases (>95%) have no definitive genetic cause. Many risk-associated genes (>26) have been identified, but the role of most of them in AD pathogenesis remains very poorly understood. Microglia are resident innate immune cells that mediate persistent neuroinflammatory responses to Aβ protein characterized by increased inflammatory cytokine production, synapse loss and neurotoxicity. Many of the identified risk-associated genes appear to encode proteins that are expressed in microglia and involved in phagocytosis and endolysosomal trafficking and proteolytic degradation, raising the possibility that fundamental abnormalities in microglia may contribute to poor Aβ processing and persistent neuroinflammation that leads to neurotoxicity and neurodegeneration in AD. Angiotensin Converting Enzyme (ACE) is a very poorly studied risk-associated gene. Previous studies published by us and strong preliminary data indicate that it has a significant role in Aβ clearance from the brain and in enhancing Aβ protein phagocytosis, its endolysosomal trafficking and proteolytic degradation in microglia. The project is outlined in three specific aims to: (1) examine the role of ACE specifically in microglia in novel transgenic mice and in an animal model of AD, (2) examine the molecular mechanisms of ACE- regulated gene expression in microglia and determine their role in phagocytosis, endolysosomal trafficking and proteolytic degradation and (3) characterize the function of ACE in human induced microglia engrafted into mice brains to study their response in vivo in a model of AD. Millions of humans are afflicted with AD, yet prevention and treatment remain very poor. We anticipate that these studies focused on the AD risk-associated gene ACE and its role in Aβ processing in microglia will identify novel signaling pathways that enhance Aβ protein processing. Moreover, we anticipate that these studies may elucidate mechanisms in microglia that may be exploited to develop treatments to enhance Aβ proteostasis and mitigate neuroinflammation in the brain in AD.