Orexin receptors exert a neuroprotective effect in Alzheimer's disease (AD) via heterodimerization with GPR103.
Orexin receptors exert a neuroprotective effect in Alzheimer's disease (AD) via heterodimerization with GPR103.
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DOI：
10.1038/srep12584
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发表时间：
2015-07-30
影响因子：
4.6
通讯作者：
Karteris E
中科院分区：
文献类型：
--
作者：
Davies J;Chen J;Pink R;Carter D;Saunders N;Sotiriadis G;Bai B;Pan Y;Howlett D;Payne A;Randeva H;Karteris E
食欲素是调节睡眠-觉醒周期和进食行为的神经肽。QRFP是一种新发现的神经肽，具有类似的促食欲活性，因此在能量平衡和食欲调节中起重要作用。QRFP及其受体GPR 103的确切表达和信号特征以及生理作用知之甚少。阿尔茨海默病（AD）患者经历夜间活动增加、白天过度嗜睡和体重减轻。因此，我们推测食欲素和QRFP可能与AD的病理生理学有关。我们报告了早发性家族性AD（EOFAD）和晚发性家族性AD（LOAD）患者海马食欲素受体（OXRs）和GPR 103的下调，特别是在角氨（CA）子区。使用体外模型，我们证明这种下调是由于Aβ-斑块形成和tau过度磷酸化。转录组学揭示了食欲素和QRFP的神经保护作用。最后，我们使用BRET和FRET提供了决定性的证据，OXRs和GPR 103形成功能性异源二聚体，发挥其作用，涉及ERK 1/2的激活。针对食欲系统的药理学干预可能被证明是发现AD等疾病的新疗法和改善神经保护信号通路的有吸引力的途径。
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.