Ghrelin System Deficiency and Hippocampal Lesions in Alzheimer's Disease

Alzheimer’s Disease (AD) is a chronic neurodegenerative disorder that primarily affects the senior population and is characterized by insidious onset and progressive cognitive decline. AD is neuropathologically defined by Amyloid beta (Aβ) deposition, abnormal Tau phosphorylation, and neurodegeneration. In addition to these pathological features, synaptic injury in the hippocampus also constitutes an early and prominent characteristic of AD brains. The severity of hippocampal synaptic failure is closely associated with cognitive impairment in patients suffering from this neurodegenerative disorder. To date, the detailed molecular mechanisms conferring hippocampal synaptic vulnerability to Aβ toxicity in AD remain elusive and as a result, effective therapies targeting hippocampal synaptic deficits in AD are as of yet unavailable. Ghrelin, the endogenous ligand for the growth hormone secretagogue receptor (GHSR), is a peptide found in both the gastrointestinal (GI) tract and in the brain. Previous studies on the ghrelin system predominantly focused on its functions in the GI tract, which include orexigenic, adipogenic, and somatotrophic properties. In recent years, the critical role of GHSR1α, the bioactive isoform of GHSR in maintaining hippocampal synaptic physiology has received increasing recognition. GHSR1α functions in modulating hippocampal synaptic activity largely through its regulation of dopamine receptor D1 (DRD1) by forming GHSR1α/DRD1 heterodimers. This dissertation addresses the critical question of whether the deregulation of GHSR is part of a key mechanism that causes hippocampal synaptic injury in AD-relevant pathological settings. Through observations of postmortem brain tissues and a mouse model mimicking AD-like amyloidosis (5×FAD mice), we unexpectedly found elevated levels of GHSR1α in the hippocampi of both AD patients and 5×FAD mice. However, further pathological and biochemical studies showed compromised GHSR1α function in Aβ-rich milieus, demonstrated by diminished GHSR1α response to its agonists. Furthermore, both AD patients and 5×FAD mice also exhibited reduced heterodimerization of GHSR1α with DRD1 in their hippocampi, despite preserved DRD1 expression levels. Consistent with the strong correlation between compromised GHSR1α function and Aβ levels, GHSR1α deregulation is, at least in part, a result of its physical binding with Aβ. This, along with AD-like hippocampal synaptic injuries in mice with genetic depletion of GHSR, adds credit to the hypothesis that GHSR1α dysfunction contributes to hippocampal synaptic lesions in AD, thereby indicating GHSR1α as a potential target for AD therapy. Despite this logical progression, our attempts to rescue hippocampal synaptic function by applying ghrelin or other GHSR agonists failed. In contrast, the co-activation of GHSR and DRD1 by a mixture of MK0677 (a specific GHSR agonist) and SKF81297 (a specific DRD1 agonist) restored GHSR1α response to agonist induced activation and protected against Aβ-mediated deficits in hippocampal synaptic function and mouse spatial learning and memory. In addition, the simultaneous application of a mixture of other GHSR1α and DRD1 agonists demonstrated a similar protective effect against Aβ-induced synaptic loss in primary hippocampal neuron cultures, further supporting the role of impaired GHSR1α regulation of DRD1 in the development of hippocampal synaptic injury in AD-related conditions. Collectively, our results suggest that GHSR1α deregulation contributes to hippocampal synaptic deficits and cognitive impairment in AD. The co-activation of GHSR1α and DRD1 holds promise in becoming a novel therapeutic avenue for the treatment of this devastating neurological disorder. Moreover, our study highlights the importance of GHSR1α’s regulation of DRD1 in hippocampal synaptic physiology.