Nutrient sensing ghrelin signaling - a novel pathogenic factor for Alzheimer’s Disease

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Project Summary Justification of the supplement: This application is in response to NOT-AG-20-034, which calls new research initiatives on Alzheimer's disease (AD). My funded NIA grant (1R01AG064869), entitled “Nutrient-sensing GHS-R in macrophage reprogramming and inflamm- aging”, 7/1/2019- 4/30/2024, is not AD-focused. It investigates the roles of ghrelin receptor GHS- R in macrophage reprogramming in liver and adipose tissues during aging, focusing on immuno- metabolic regulation in peripheral tissues. Aging is associated with metabolic decline and increased inflammation throughout the body. Emerging evidence shows that neuroinflammation has major roles in pathogenesis of AD. In this supplement, we aim to study the role of GHS-R in metabolic reprogramming of microglia in AD. This supplement provides a new immuno-metabolic angle to the AD field, shedding light on a novel role of GHS-R in AD. We believe that this supplement is within the general scope of the funded R01, but expands into an exciting new aspect of AD which is both complementary and synergistic with the NIA funded grant. Scope of the supplement: We have reported that global ablation of GHS-R improves aging metabolism and mitigates systemic inflammation in aging, showing anti-inflammatory macrophage polarization. Microglia are the primary drivers of neuroinflammation, our preliminary data showed that GHS-R expression in microglia is drastically increased by AD-priming endotoxin lipopolysaccharides (LPS) and GHS-R antagonist suppresses LPS-induced inflammation in macroglia. We hypothesize that GHS-R is a pathogenic factor for AD; GHS-R promotes pro- inflammatory activation and polarization of microglia to exacerbate neuroinflammation in AD. We will study microglial GHS-R deficient 5XFAD mice (Cx3cr1CreER;Ghsrflox/flox; 5XFAD) via the following Specific Aims: Aim 1. Determine the role of microglial GHS-R on learning and memory, neuroinflammation, and AD pathology. Aim 2. Determine the polarization state, cellular/molecular signatures, and regulatory mechanisms of GHS-R deficient microglia in AD. The impact of the supplement: This supplemental funding will provide us with the much- needed support to investigate our new hypothesis. Our unique mouse model and solid preliminary data combined with our expertise in immunology and aging metabolism offer strong scientific premise and high feasibility for success. We are confident that we will successfully complete the proposed studies with the support of the award. Results from current proposal will set the stage for a full-fledged project in further mechanistic investigation of nutrient–sensing GHS-R in AD, which has potential to lead to novel immunotherapeutic interventions for AD.