Disrupted hippocampal growth hormone secretagogue receptor 1α interaction with dopamine receptor D1 plays a role in Alzheimer's disease

Hippocampal lesions are a defining pathology of Alzheimer's disease (AD). However, the molecular mechanisms that underlie hippocampal synaptic injury in AD have not been fully elucidated. Current therapeutic efforts for AD treatment are not effective in correcting hippocampal synaptic deficits. Growth hormone secretagogue receptor 1 alpha (GHSR1 alpha) is critical for hippocampal synaptic physiology. Here, we report that GHSR1 alpha interaction with beta-amyloid (A beta) suppresses GHSR1 alpha activation, leading to compromised GHSR1 alpha regulation of dopamine receptor D1 (DRD1) in the hippocampus from patients with AD. The simultaneous application of the selective GHSR1 alpha agonist MK0677 with the selective DRD1 agonist SKF81297 rescued Ghsr1 alpha function from A. inhibition, mitigating hippocampal synaptic injury and improving spatial memory in an AD mouse model. Our data reveal a mechanism of hippocampal vulnerability in AD and suggest that a combined activation of GHSR1 alpha and DRD1 may be a promising approach for treating AD.