Orexin receptors exert a neuroprotective effect in Alzheimer's disease (AD) via heterodimerization with GPR103

Davies, Julie, Chen, Jing, Pink, Ryan, Carter, David, Saunders, Nigel, Sotiriadis, Georgios, Bai, Bo, Pan, Yanyou, Howlett, David, Payne, Annette, Randeva, Harpal and Karteris, Emmanouil (2015). Orexin receptors exert a neuroprotective effect in Alzheimer's disease (AD) via heterodimerization with GPR103. Scientific Reports, 5 ,

Abstract

Orexins are neuropeptides that regulate the sleep-wake cycle and feeding behaviour. QRFP is a newly discovered neuropeptide which exerts similar orexigenic activity, thus playing an important role in energy homeostasis and regulation of appetite. The exact expression and signalling characteristics and physiological actions of QRFP and its receptor GPR103 are poorly understood. Alzheimerâ €™ s disease (AD) patients experience increased nocturnal activity, excessive daytime sleepiness, and weight loss. We hypothesised therefore that orexins and QRFP might be implicated in the pathophysiology of AD. We report that the down-regulation of hippocampal orexin receptors (OXRs) and GPR103 particularly in the cornu ammonis (CA) subfield from AD patients suffering from early onset familial AD (EOFAD) and late onset familial AD (LOAD). Using an in vitro model we demonstrate that this downregulation is due to to Aβ-plaque formation and tau hyper-phosphorylation. Transcriptomics revealed a neuroprotective role for both orexins and QRFP. Finally we provide conclusive evidence using BRET and FRET that OXRs and GPR103 form functional hetero-dimers to exert their effects involving activation of ERK 1/2. Pharmacological intervention directed at the orexigenic system may prove to be an attractive avenue towards the discovery of novel therapeutics for diseases such as AD and improving neuroprotective signalling pathways.

Publication DOI: https://doi.org/10.1038/srep12584
Divisions: Aston Medical School
Additional Information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ Supplementary information: http://www.nature.com/srep
Uncontrolled Keywords: General
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
Published Date: 2015-07-30
Authors: Davies, Julie
Chen, Jing
Pink, Ryan
Carter, David
Saunders, Nigel
Sotiriadis, Georgios
Bai, Bo
Pan, Yanyou
Howlett, David
Payne, Annette
Randeva, Harpal
Karteris, Emmanouil

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