title: Orexin receptors exert a neuroprotective effect in Alzheimer's disease (AD) via heterodimerization with GPR103.
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.
authors.affiliation: Biosciences, College of Health and Life Sciences, Brunel University, Uxbridge, UB8 3PH, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Davies
authors.affiliation: 1] Division of Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK [2] Neurobiology Institute, Jining Medical University, Jining, Shandong, 272067, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Biological and Medical Sciences, Oxford Brookes University, UK.
authors.forename: Ryan
authors.initials: R
authors.lastname: Pink
authors.affiliation: Department of Biological and Medical Sciences, Oxford Brookes University, UK.
authors.forename: David
authors.initials: D
authors.lastname: Carter
authors.affiliation: Centre for Systems and Synthetic Biology, Brunel University, Uxbridge UB83PH, UK.
authors.forename: Nigel
authors.initials: N
authors.lastname: Saunders
authors.affiliation: Biosciences, College of Health and Life Sciences, Brunel University, Uxbridge, UB8 3PH, UK.
authors.forename: Georgios
authors.initials: G
authors.lastname: Sotiriadis
authors.affiliation: Neurobiology Institute, Jining Medical University, Jining, Shandong, 272067, P.R. China.
authors.forename: Bo
authors.initials: B
authors.lastname: Bai
authors.affiliation: Neurobiology Institute, Jining Medical University, Jining, Shandong, 272067, P.R. China.
authors.forename: Yanyou
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Wolfson Centre for Age Related Diseases, King's College London, London, SE11UL, UK.
authors.forename: David
authors.initials: D
authors.lastname: Howlett
authors.affiliation: Department of Computer Science, College of Engineering, Design and Physical Sciences, Brunel University, Uxbridge UB8 3PH, UK.
authors.forename: Annette
authors.initials: A
authors.lastname: Payne
authors.affiliation: 1] Division of Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK [2] Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham, B4 7ET, UK.
authors.forename: Harpal
authors.initials: H
authors.lastname: Randeva
authors.affiliation: Biosciences, College of Health and Life Sciences, Brunel University, Uxbridge, UB8 3PH, UK.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Karteris
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D000682:Amyloid / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D019281:Dimerization; D015536:Down-Regulation; D031541:Fluorescence Resonance Energy Transfer; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D064446:Orexin Receptors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology; D019287:Zinc Sulfate / Q000494:pharmacology; D016875:tau Proteins / Q000378:metabolism
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D064446:Orexin Receptors; D010446:Peptide Fragments; C476582:QRFPR protein, human; D043562:Receptors, G-Protein-Coupled; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D014212:Tretinoin; D019287:Zinc Sulfate; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3