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

Julie Davies, Jing Chen, Ryan Pink, David Carter, Nigel Saunders, Georgios Sotiriadis, Bo Bai, Yanyou Pan, David Howlett, Annette Payne, Harpal Randeva, Emmanouil Karteris*

*Corresponding author for this work

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number12584
Number of pages12
JournalScientific Reports
Volume5
DOIs
Publication statusPublished - 30 Jul 2015

Bibliographical note

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Supplementary information: http://www.nature.com/srep

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    Davies, J., Chen, J., Pink, R., Carter, D., Saunders, N., Sotiriadis, G., Bai, B., Pan, Y., Howlett, D., Payne, A., Randeva, H., & Karteris, E. (2015). Orexin receptors exert a neuroprotective effect in Alzheimer's disease (AD) via heterodimerization with GPR103. Scientific Reports, 5, [12584]. https://doi.org/10.1038/srep12584