Project Abstract/Summary The worldwide prevalence of obesity has reached pandemic proportions. Obesity has strong inflammatory underpinnings, which are associated with the development of chronic inflammatory diseases, including Alzheimer’s disease (AD). However, the mechanisms by which obesity provokes aberrant inflammation are not clearly defined. Obesity-induced hepatosteatosis is frequently accompanied by hepatic insulin resistance, subsequently causing hyperinsulinemia. In our parent R01 study, we aim to demonstrate that in obesity, hyperinsulinemia enhances the biogenesis and secretion of pro-inflammatory extracellular vesicles (EVs) and that EVs cause aberrant inflammation. In this Administrative Supplements (NOT-AG-20-034), we propose to investigate the pathogenesis of AD by applying our findings and experimental tools used in researching pro- inflammatory EVs. We hypothesize that in obesity, EVs become pro-inflammatory and induces abnormal inflammatory responses even in the brain, which contribute to the development of AD. As recent evidence suggests, an important role of liver function is in the pathophysiology of AD, and so we hypothesize that H-EVs under obesity and hyperinsulinemia mediate the pathophysiology of AD. These preliminary results led us to the hypotheses: (1) during the development of hyperinsulinemia, hepatocytes secrete pathologic, pro-inflammatory EVs, and (2) these pro-inflammatory EVs are uptaken by cells in the brain leading to aberrant inflammation. To test this, we will pursue the following Aims: Studies in this proposal will: (1) determine recipient cells of EVs in the brain and their inflammatory status, and (2) determine the role of APOE genetic variants in the pro-inflammatory traits of EVs. This study would be a critical step addressing these unsolved questions of how obesity and hyperinsulinemia are associated with the development of AD and identifying potential therapeutic targets for preventing and treating AD in humans.