Suvorexant Acutely Decreases Tau Phosphorylation and Aβ in the Human CNS.
Suvorexant Acutely Decreases Tau Phosphorylation and Aβ in the Human CNS.
复制标题
Suvorexant 急剧降低人类中枢神经系统中的 Tau 磷酸化和 Aβ。
DOI：
10.1002/ana.26641
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发表时间：
2023
影响因子：
11.2
通讯作者：
Bateman,RandallJ
中科院分区：
文献类型：
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作者：
Lucey,BrendanP;Liu,Haiyan;Toedebusch,CristinaD;Freund,David;Redrick,Tiara;Chahin,SamirL;Mawuenyega,KwasiG;Bollinger,JamesG;Ovod,Vitaliy;Barthélemy,NicolasR;Bateman,RandallJ
在阿尔茨海默病中，过度磷酸化的tau蛋白与不溶性成对螺旋丝的形成有关，这些螺旋丝聚集为神经元性tau蛋白缠结，并与神经元损失和认知症状有关。双重食欲素受体拮抗剂降低过表达淀粉样蛋白β的小鼠模型中可溶性淀粉样蛋白β水平和淀粉样蛋白斑块，但尚未报道影响tau磷酸化。在这项随机对照试验中，我们测试了苏沃雷生，一种双重食欲素受体拮抗剂，对淀粉样蛋白β，tau蛋白和磷酸化tau蛋白的急性作用。Methods 38名年龄在45至65岁的认知功能未受损的参与者被随机分配到安慰剂组（N = 13），苏沃雷生10 mg（N = 13）和苏沃雷生20 mg（N = 12）。从20：00开始，每2小时通过留置腰椎导管收集6毫升脑脊液，持续36小时。受试者在21：00接受安慰剂或苏沃雷生。所有样本均经过处理，并通过免疫沉淀和液相色谱-质谱法测量多种形式的淀粉样蛋白-β、tau和磷酸化-tau。结果磷酸化-tau-threonine-181与未磷酸化-tau-threonine-181的比率（该tau磷酸化位点的磷酸化指标）与安慰剂相比，接受苏沃雷生20 mg治疗的参与者降低了约10%至15%。然而，苏沃雷生未降低tau-丝氨酸-202和tau-苏氨酸-217的磷酸化。与安慰剂相比，苏沃雷生在给药后5小时开始降低β淀粉样蛋白约10%至20%.Interpretation在本研究中，苏沃雷生急性降低了中枢神经系统中tau蛋白磷酸化和β淀粉样蛋白浓度。Suvorexant已被美国食品和药物管理局批准用于治疗失眠，并可能成为预防阿尔茨海默病的再利用药物，但需要进一步进行长期治疗研究。神经网络2023;94：27-40
ObjectiveIn Alzheimer's disease, hyperphosphorylated tau is associated with formation of insoluble paired helical filaments that aggregate as neurofibrillary tau tangles and are associated with neuronal loss and cognitive symptoms. Dual orexin receptor antagonists decrease soluble amyloid‐β levels and amyloid plaques in mouse models overexpressing amyloid‐β, but have not been reported to affect tau phosphorylation. In this randomized controlled trial, we tested the acute effect of suvorexant, a dual orexin receptor antagonist, on amyloid‐β, tau, and phospho‐tau.MethodsThirty‐eight cognitively unimpaired participants aged 45 to 65 years were randomized to placebo (N = 13), suvorexant 10 mg (N = 13), and suvorexant 20 mg (N = 12). Six milliliters of cerebrospinal fluid were collected via an indwelling lumbar catheter every 2 hours for 36 hours starting at 20:00. Participants received placebo or suvorexant at 21:00. All samples were processed and measured for multiple forms of amyloid‐β, tau, and phospho‐tau via immunoprecipitation and liquid chromatography‐mass spectrometry.ResultsThe ratio of phosphorylated‐tau‐threonine‐181 to unphosphorylated‐tau‐threonine‐181, a measure of phosphorylation at this tau phosphosite, decreased ~10% to 15% in participants treated with suvorexant 20 mg compared to placebo. However, phosphorylation at tau‐serine‐202 and tau‐threonine‐217 were not decreased by suvorexant. Suvorexant decreased amyloid‐β ~10% to 20% compared to placebo starting 5 hours after drug administration.InterpretationIn this study, suvorexant acutely decreased tau phosphorylation and amyloid‐β concentrations in the central nervous system. Suvorexant is approved by the US Food and Drug Administration to treatment insomnia and may have potential as a repurposed drug for the prevention of Alzheimer's disease, however, future studies with chronic treatment are needed. ANN NEUROL 2023;94:27–40