Supplement: The Interaction of Interleukin 1b and Glucocorticoid Signaling Pathways in Alzheimer's Disease

The parent grant is focused on studying the IL-1s/GR interaction in hepatocytes in the context of hepatic steatosis. In this application for administrative supplement, we would like to expand the scope of the studies beyond hepatocytes and to test our hypothesis in neurons and astrocytes in the context of Alzheimer¡¦s Disease (AD). The premise of the new experiments is: (i) both, IL-1s and GR have a substantial impact on brain function and have been implicated in the onset of inflammatory milieu and cognitive decline during AD; (ii) solid evidence from AD animal models and human patients supports the notion that brain IL-1s levels increase in the course of AD; importantly the changes in IL-1ƒÒ are seemingly more pronounced that those of other cytokines, illustrating the importance of IL-1ƒÒ to AD pathology; (iii) the preliminary data included herein indicate an abnormal level of GR in the area of amyloid plaques in the 5xFAD mouse model of AD, emphasizing the need to investigate the mechanisms responsible for these increases and the consequences for metabolism and cognition; (iv) Neutral Sphingomyelinase-2 (NSMase-2), a key mediator of the IL-1ƒÒ/GR interaction, has been causatively implicated in AD progression. We will test the proposed hypothesis in two specific aims: Aim 1: Evaluate the contribution of IL- 1ƒÒ and nSMase-2 to GR up-regulation in Alzheimer disease mouse model. Aim 2: Evaluate IL-1ƒÒ impact on GR-dependent gene regulation in neurons and astrocytes ex vivo. Glucocorticoids are essential hormonal regulator of numerous brain functions. Solid evidence exists to document altered GC signaling during AD. Better understanding the impact of proinflammatory environment in the AD brain on glucocorticoid signaling will bring novel understanding on the mechanisms for metabolic changes in AD.