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Orexin-A aggravates cognitive dysfunction and increases amyloid \u03b2 (A\u03b2) 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 A\u03b2 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 A\u03b2 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.<\/jats:p>","DOI":"10.1093\/gerona\/glae115","type":"journal-article","created":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T08:19:03Z","timestamp":1714378743000},"source":"Crossref","is-referenced-by-count":8,"title":["Selective Orexin 2 Receptor Blockade Alleviates Cognitive Impairments and the Pathological Progression of Alzheimer\u2019s Disease in 3xTg-AD Mice"],"prefix":"10.1093","volume":"79","author":[{"given":"Xiao-Hong","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Key Laboratory of Cellular Physiology in Shanxi Province, Shanxi Medical University , Taiyuan , People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai-Yue","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Key Laboratory of Cellular Physiology in Shanxi Province, Shanxi Medical University , Taiyuan , People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Xin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Key Laboratory of Cellular Physiology in Shanxi Province, Shanxi Medical University , Taiyuan , People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Nan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Key Laboratory of Cellular Physiology in Shanxi Province, Shanxi Medical University , Taiyuan , People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan-Juan","family":"Jiao","sequence":"additional","affiliation":[{"name":"Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Key Laboratory of Cellular Physiology in Shanxi Province, Shanxi Medical University , Taiyuan , People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao-Jun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Key Laboratory of Cellular Physiology in Shanxi Province, Shanxi Medical University , Taiyuan , People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Yan","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Shanxi Medical University , Taiyuan, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, Shanxi Bethune Hospital , Taiyuan, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye-Xin","family":"He","sequence":"additional","affiliation":[{"name":"Department of Radiology, Shanxi Provincial People\u2019s Hospital , Taiyuan, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei-Na","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Key Laboratory of Cellular Physiology in Shanxi 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