Intercellular mechanisms of microglia activation in diet-induced obesity

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This is an administrative supplement request (PA-18-591) in response to NOT-AG-20-034 (Alzheimer's -focused Administrative supplements for NIH grants that are not focused on Alzheimer's disease) to our ongoing NIH grant 1R01DK120321-03 entitled “Intracellular mechanisms of microglia activation in diet-induced obesity”. This project aims to unmask the role of uncoupling protein 2 (UCP2)-mediated mitochondrial dynamics in microglia activation in the central regulation of energy homeostasis in order to develop better strategies for the treatment of metabolic disorders, such as obesity and type 2 diabetes. There are no Alzheimer’s Disease-related studies proposed in this grant. In response to NOT-AG-20-034, we request funds to test the hypothesis that UCP2-dependent microglia activation and neuroinflammation may impact the onset of the development of Alzheimer’s disease (AD) in genetic mouse model of AD by affecting histological and behavioral changes. Our preliminary studies show that inhibiting UCP2-dependent microglia activation in mice exposed to HFD feeding prevents neuroinflammation (microgliosis), protects from the development of metabolic disorders, such as obesity and type 2 diabetes, and also prevents changes in behaviors and hippocampal structure that are associated with aging and AD. As aging and obesity are risk factors for the development of neurodegenerative disorders such as Alzheimer’s disease (AD), we hypothesize that HFD-induced UCP2-dependent microglia activation plays a role in the onset of the development of AD and inhibition of this mechanism, by reducing chronic neuroinflammation, prevents and/or delays the onset of cortical and hippocampal histological and behavioral changes in AD. Thus, in this supplement we propose to assess the effect of selective and inducible deletion of UCP2 in microglial cells on the histology and behavior of AD mice [5xFAD mice (B6.Cg- Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax; Oakley H et al., 2006)] exposed to either standard chow diet or HFD, at different time points. Several littermate mice will be used as controls. Both male and female mice will be studied. Behavioral and histological studies will be performed at different time points to assess the role of microglia in the onset of AD development in this AD mouse model. The execution of these studies will deliver novel insights into the role of microglia and metabolism in AD.