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。食欲素-A 加重了 AD 模型小鼠的认知功能障碍并增加了淀粉样蛋白 β （Aβ） 沉积，但对 AD 中不同双重食欲素受体 （OXR） 拮抗剂的研究显示结果不一致。我们之前的研究显示，OX1R 阻断会加重 3xTg-AD 小鼠的认知缺陷和病理进展，但 OX2R 的影响及其在 AD 中的潜在机制尚未见报道。在本研究中，口服选择性 OX2R 拮抗剂 MK-1064 阻断 OX2R，并通过行为测试评价 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、western blotting 和 ELISA 检测 Aβ 沉积、 tau 磷酸化和神经炎症，记录电生理和车轮运行活动记录，观察海马突触可塑性和昼夜节律。结果显示，OX2R 阻断可改善认知功能障碍，改善 LTP 抑郁，增加 PSD-95 表达，减轻 3xTg-AD 小鼠的焦虑和抑郁样行为以及昼夜节律紊乱，并减少 3xTg-AD 小鼠大脑中的 Aβ 病理、tau 磷酸化和神经炎症。这些结果表明，慢性 OX2R 阻断至少部分通过改善昼夜节律紊乱和睡眠-觉醒周期来减少 AD 病理，从而在 3xTg-AD 小鼠中发挥神经保护作用，并且 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需要进一步研究。