Abstract
Hippocampal lesions including synaptic injury, neuroinflammation, and impaired neurogenesis are featured pathology closely associated with neuronal stress and cognitive impairment in Alzheimer's disease (AD). Previous studies suggest that ghrelin and its receptor, growth hormone secretagogue receptor 1α (GHSR1α), promote hippocampal synaptic function and neurogenesis. GHSR1α activation thus holds the potential to be a therapeutic avenue for the treatment of hippocampal pathology in AD; however, a comprehensive study on the preventive effect of MK0677 on hippocampal lesions in AD-related conditions is still lacking. In this study, we treated a transgenic mouse model of AD-like amyloidosis (5xFAD mice) at the asymptomatic stage with MK0677, a potent ghrelin mimetic. We found that MK0677 fostered hippocampal neurogenesis in 5xFAD mice but observed little preventive function with regards to the development of hippocampal amyloid-β (Aβ) deposition, synaptic loss, microglial activation, or cognitive impairment. Furthermore, MK0677 at a dose of 3 mg/kg significantly increased 5xFAD mouse mortality. Despite enhanced hippocampal neurogenesis, MK0677 treatment has little beneficial effect to prevent hippocampal lesions or cognitive deficits against Aβ toxicity. This study, together with a failed large-scale clinical trial, suggests the ineffectiveness of MK0677 alone for AD prevention and treatment.