Research ArticleAlzheimer’s Disease

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

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Science Translational Medicine  14 Aug 2019:
Vol. 11, Issue 505, eaav6278
DOI: 10.1126/scitranslmed.aav6278

An appetite for memory

The hippocampus serves a critical role in memory formation and cognition. Hippocampal lesions are among the earliest changes in Alzheimer’s disease (AD); however, the molecular mechanisms responsible for these alterations remain unclear. By using autoptic brain samples from patients with AD and a mouse model of AD, Tian et al. show that in the hippocampus, pathologic β-amyloid directly binds and inhibits the receptor for the “hunger hormone” ghrelin (GHSR1α). In the animal model, the binding blocked the GHSR1α-mediated dopamine receptor D1 (DRD1) activation, leading to synaptic plasticity impairments and memory loss. Simultaneous pharmacological activation of GHSR1α and DRD1 rescued synaptic plasticity and spatial memory loss in AD mice.


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 1α (GHSR1α) is critical for hippocampal synaptic physiology. Here, we report that GHSR1α interaction with β-amyloid (Aβ) suppresses GHSR1α activation, leading to compromised GHSR1α regulation of dopamine receptor D1 (DRD1) in the hippocampus from patients with AD. The simultaneous application of the selective GHSR1α agonist MK0677 with the selective DRD1 agonist SKF81297 rescued Ghsr1α function from Aβ 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 GHSR1α and DRD1 may be a promising approach for treating AD.

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