GOAT-mediated ghrelin deregulation and hippocampal pathology in Alzheimer's Disease

University Of Kansas Lawrence, Lawrence KS

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Abstract

Project Summary: Hippocampal lesions constitute a characteristic brain pathology underlying memory loss in both familial and sporadic Alzheimer’s disease (AD). Ghrelin, a stomach-produced, acylated peptide hormone, is the endogenous agonist of growth hormone secretagogue receptor (GHSR, also known as ghrelin receptor). In addition to the importance of the ghrelin system to systemic energy homeostasis, ghrelin passes the blood-brain-barrier (BBB) to elicit hippocampal GHSR signaling for the modulation of hippocampal synaptic activity. In our last funding period, we have determined the contribution of amyloid beta (Aβ)-induced GHSR deactivation to the development of hippocampal synaptic failure and cognitive deficits in AD-related conditions. Interestingly, in contrast to decreased availability of functional hippocampal GHSR, we also observed a paradoxical increase in circulating bioactive ghrelin in both AD patients and mouse models, including a mouse model of familial AD (5xFAD mice) and a mouse model of AD risk [human Aβ knockin (hAβ KI) mice, also referred to in the literature as a mouse model of late-onset sporadic AD], indicating that ghrelin overactivation is a phenotypic change in AD-relevant pathological settings. Although ghrelin is a neurotrophic peptide that stimulates GHSR to benefit hippocampal synaptic activity, administration of a synthetic ghrelin mimetic demonstrated no protection of cognitive function in 5xFAD mice and increased mouse mortality, echoing a previous failed large-scale clinical trial. Importantly, further experiments showed that persistent ghrelin exposure induced dose-dependent GHSR desensitization by promoting GHSR internalization. Together with the well-characterized detrimental impact of ghrelin deficiency on cognition, these findings highlight the importance of normal ghrelin regulation to GHSR function in hippocampal physiology and further implicate that disrupted ghrelin homeostasis due to overactivation is an undesirable pathological event promoting hippocampal GHSR dysfunction in AD paradigms. Ghrelin O- acyltransferase (GOAT) is the key enzyme that catalyzes ghrelin activation via acylation. Not only is GOAT abundant within stomach ghrelin cells, but emerging evidence also suggests a role of plasma GOAT in the maintenance of ghrelin activity in circulation. Other emerging evidence suggests that Aβ-induced GOAT hyperactivity may be a key factor driving ghrelin overactivation in AD-related conditions. These observations, together with the importance of ghrelin to metabolism, lead us to hypothesize that ghrelin overactivation due to GOAT hyperactivity contributes to hippocampal deficits, leading to memory loss in AD. In the proposed study, we will establish a link between GOAT hyperactivity, ghrelin overactivation, and hippocampal GHSR dysfunction (Aim1), examine the impact of GOAT/ghrelin deregulation on hippocampal metabolism (Aim2), and determine the contribution of GOAT/ghrelin deregulation to hippocampal synaptic injury and cognitive impairment in familial and sporadic AD-related conditions (Aim3). The results from this study will answer important questions about the ghrelin system in AD pathogenesis, and will suggest a novel avenue for the treatment and prevention of AD.