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针对后突触蛋白质组具有治疗阿尔茨海默病精神病的治疗潜力

J M Krivinko¹, M R DeChellis-Marks², L Zeng³

¹Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Communications biology

|June 2, 2023

概括

患有阿尔茨海默氏症加上精神病 (AD+P) 的个体表现出突触蛋白质的改变. C-C 基因化学物质受体5抑制剂马拉维罗克在小鼠中逆转了这些变化,这表明了AD+P的潜在新疗法.

科学领域:

神经科学是一个神经科学.
蛋白质组学是指蛋白质组学.
药理学药理学是指药理学的学科.

背景情况:

与没有精神病的阿尔茨海默氏症 (AD-P) 相比,带有精神病症状 (AD+P) 的阿尔茨海默氏症与加速的认知衰退和突触完整性受损有关.
突触后密度 (PSD) 对突触功能和可塑性至关重要,其蛋白质组合可能在AD+P中发生变化.

研究的目的:

与AD-P和认知正常对照相比,研究AD+P患者的PSD蛋白质组的变化.
确定潜在的治疗点,可以逆转AD+P中观察到的PSD蛋白质变化.

主要方法:

从三组人类受试者的背侧前额皮质中分离出来的PSD的蛋白质组分析:AD+P,AD-P和对照.
计算分析以识别潜在的治疗药物,预测可以逆转PSD蛋白质组特征.
在成年小鼠模型中对候选药物 (maraviroc) 的体内验证.

主要成果:

与AD-P相比,AD+P中的PSD蛋白质组显示出蛋白质水平的总体降低.
丰富分析揭示了AD+PPSD蛋白质组内的激酶,Rho GTPase调节剂和actin细胞骨蛋白质的显著变化.
用马拉维罗克 (C-C 基因化学因子受体5抑制剂) 治疗诱导了小鼠PSD蛋白质组特征的逆转.

结论:

阿尔茨海默病中精神病症状与PSD蛋白质组的广泛变化有关,特别是影响突触调节蛋白.
马拉维罗克通过扭转后突触密度中的关键分子缺陷,显示出作为AD+P新型治疗剂的潜力.

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