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Orexin receptors exert a neuroprotective effect in Alzheimer’s disease (AD) via heterodimerization with GPR103
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Davies, Julie, Chen, Jing, Pink, Ryan, Carter, David, Saunders, Nigel, Sotiriadis, Georgios, Bai, Bo, Pan, Yanyou, Howlett, David, Payne, Annette, Randeva, Harpal S. and Karteris, Emmanouil (2015) Orexin receptors exert a neuroprotective effect in Alzheimer’s disease (AD) via heterodimerization with GPR103. Scientific Reports, 5 . pp. 1-12. 12584. doi:10.1038/srep12584 ISSN 2045-2322.
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Official URL: http://dx.doi.org/10.1038/srep12584
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. Alzheimer’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 ERK1/2. 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.
Item Type: | Journal Article | ||||||||
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Subjects: | R Medicine > RC Internal medicine | ||||||||
Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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Library of Congress Subject Headings (LCSH): | Alzheimer's disease, Orexins | ||||||||
Journal or Publication Title: | Scientific Reports | ||||||||
Publisher: | Nature Publishing Group | ||||||||
ISSN: | 2045-2322 | ||||||||
Official Date: | 30 July 2015 | ||||||||
Dates: |
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Volume: | 5 | ||||||||
Number of Pages: | 12 | ||||||||
Page Range: | pp. 1-12 | ||||||||
Article Number: | 12584 | ||||||||
DOI: | 10.1038/srep12584 | ||||||||
Status: | Peer Reviewed | ||||||||
Publication Status: | Published | ||||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||||
Date of first compliant deposit: | 31 December 2015 | ||||||||
Date of first compliant Open Access: | 31 December 2015 |
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