PDF(Pubmed)
Abstract：
Alzheimer\'s disease (AD) remains a significant health challenge, with an increasing prevalence globally. Recent research has aimed to deepen the understanding of the disease pathophysiology and to find potential therapeutic interventions. In this regard, G protein-coupled receptors (GPCRs) have emerged as novel potential therapeutic targets to palliate the progression of neurodegenerative diseases such as AD. Orexin and cannabinoid receptors are GPCRs capable of forming heteromeric complexes with a relevant role in the development of this disease. On the one hand, the hyperactivation of the orexins system has been associated with sleep-wake cycle disruption and Aβ peptide accumulation. On the other hand, cannabinoid receptor overexpression takes place in a neuroinflammatory environment, favoring neuroprotective effects. Considering the high number of interactions between cannabinoid and orexin systems that have been described, regulation of this interplay emerges as a new focus of research. In fact, in microglial primary cultures of APPSw/Ind mice model of AD there is an important increase in CB2R-OX1R complex expression, while OX1R antagonism potentiates the neuroprotective effects of CB2R. Specifically, pretreatment with the OX1R antagonist has been shown to strongly potentiate CB2R signaling in the cAMP pathway. Furthermore, the blockade of OX1R can also abolish the detrimental effects of OX1R overactivation in AD. In this sense, CB2R-OX1R becomes a new potential therapeutic target to combat AD.
摘要：
阿尔茨海默病（AD）仍然是一个重大的健康挑战，随着全球患病率的增加。最近的研究旨在加深对疾病病理生理学的理解，并找到潜在的治疗干预措施。在这方面,G蛋白偶联受体（GPCRs）已成为新的潜在治疗靶标，以减轻神经退行性疾病如AD的进展。食欲素和大麻素受体是能够形成异聚复合物的GPCRs，在该疾病的发展中起相关作用。一方面,食欲素系统的过度激活与睡眠-觉醒周期中断和Aβ肽积累有关。另一方面,大麻素受体过度表达发生在神经炎症环境中，有利于神经保护作用。考虑到已经描述的大麻素和食欲素系统之间的大量相互作用，对这种相互作用的调节成为一个新的研究热点。事实上,在APPSw/Ind小鼠模型的小胶质细胞原代培养物中，CB2R-OX1R复合物表达有重要增加，而OX1R拮抗作用增强了CB2R的神经保护作用。具体来说,用OX1R拮抗剂预处理已被证明可以强烈增强cAMP途径中的CB2R信号传导。此外，阻断OX1R还可以消除AD中OX1R过度激活的有害作用。在这个意义上,CB2R-OX1R成为对抗AD的新的潜在治疗靶点。
