Ghrelin Receptor Mediated Neuroinflammation in Alzheimer’s Disease

Project Summary

Alzheimer’s disease (AD) is a devastating neurodegenerative disease with no effective treatment. Emerging evidences suggest that neuroinflammation has a major role in the pathogenesis of AD. Neuroinflammation is mediated by myeloid cells in the brain, which consist of resident microglia and infiltrating monocyte-derived macrophages (mo-Mf) recruited from circulation upon stress/injury.  Similar to peripheral macrophages, microglia and mo-Mf cells are highly plastic and dynamic, shifting from resting state to activated state in response to environmental insults. Activated pro-inflammatory microglia/mo-Mf cells produce pro-inflammatory cytokines that elicit neuropathology. Understanding the activation and polarization of microglia and mo-Mf is of great importance in combating neuroinflammation in AD. Ghrelin receptor, growth hormone secretagogue receptor (GHS-R), is an important nutrient sensor and metabolic regulator. We showed that GHS-R is abundantly expressed in macrophages; its expression in macrophages increases during aging and under high fat diet (HFD) feeding. We have reported that global ablation of GHS-R mitigates systemic inflammation in aging, showing anti-inflammatory macrophage polarization. To study the specific effect of GHS-R in myeloid cells, we generated myeloid-specific GHS-R deficient mice (LysM-Cre;Ghsrflox/flox). We will carry out the following specific studies: 1. Determine the effects of myeloid GHS-R deficiency on neuroinflammation and AD pathology. 2. Determine the molecular signatures and regulatory mechanisms of GHS-R deficient microglia/mo-Mf cells.  We anticipate that novel immunotherapy of targeting GHS-R in myeloid cells likely have potential to reprogram myeloid cells in the brain to combat AD.