The orexin system is closely related to the pathogenesis of Alzheimer's disease (AD). Orexin-A aggravates cognitive dysfunction and increases amyloid β (Aβ) deposition in AD model mice, but studies of different dual orexin receptor (OXR) antagonists in AD have shown inconsistent results. Our previous study revealed that OX1R blockade aggravates cognitive deficits and pathological progression in 3xTg-AD mice, but the effects of OX2R and its potential mechanism in AD have not been reported. In the present study, OX2R was blocked by oral administration of the selective OX2R antagonist MK-1064, and the effects of OX2R blockade on cognitive dysfunction and neuropsychiatric symptoms in 3xTg-AD mice were evaluated via behavioral tests. Then, immunohistochemistry, western blotting and ELISA were used to detect Aβ deposition, tau phosphorylation and neuroinflammation, and electrophysiological and wheel-running activity recording were recorded to observe hippocampal synaptic plasticity and circadian rhythm. The results showed that OX2R blockade ameliorated cognitive dysfunction, improved LTP depression, increased the expression of PSD-95, alleviated anxiety- and depression-like behaviors and circadian rhythm disturbances in 3xTg-AD mice, and reduced Aβ pathology, tau phosphorylation and neuroinflammation in the brains of 3xTg-AD mice. These results indicated that chronic OX2R blockade exerts neuroprotective effects in 3xTg-AD mice by reducing AD pathology at least partly through improving circadian rhythm disturbance and the sleep-wake cycle and that OX2R might be a potential target for the prevention and treatment of AD; however, the potential mechanism by which OX2R exerts neuroprotective effects on AD needs to be further investigated.

中文翻译：

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选择性食欲素 2 受体阻断可减轻 3xTg-AD 小鼠的认知障碍和阿尔茨海默病的病理进展

食欲素系统与阿尔茨海默病（AD）的发病机制密切相关。 Orexin-A 会加重 AD 模型小鼠的认知功能障碍并增加淀粉样蛋白 β (Aβ) 沉积，但对不同双食欲素受体 (OXR) 拮抗剂治疗 AD 的研究显示出不一致的结果。我们之前的研究表明，OX1R 阻断会加重 3xTg-AD 小鼠的认知缺陷和病理进展，但 OX2R 的作用及其在 AD 中的潜在机制尚未报道。在本研究中，通过口服选择性OX2R拮抗剂MK-1064来阻断OX2R，并通过行为测试评估OX2R阻断对3xTg-AD小鼠认知功能障碍和神经精神症状的影响。然后采用免疫组化、蛋白质印迹和ELISA检测Aβ沉积、tau磷酸化和神经炎症，并记录电生理和跑轮活动记录以观察海马突触可塑性和昼夜节律。结果表明，OX2R 阻断可改善 3xTg-AD 小鼠的认知功能障碍，改善 LTP 抑郁，增加 PSD-95 的表达，减轻焦虑和抑郁样行为以及昼夜节律紊乱，并减少 3xTg-AD 小鼠的 Aβ 病理、tau 磷酸化和神经炎症。 3xTg-AD 小鼠的大脑。这些结果表明，长期阻断 OX2R 至少部分通过改善昼夜节律紊乱和睡眠-觉醒周期来减轻 AD 病理，从而对 3xTg-AD 小鼠发挥神经保护作用，OX2R 可能是预防和治疗 AD 的潜在靶点；然而，OX2R对AD发挥神经保护作用的潜在机制还需要进一步研究。