昼夜节律和光暗周期相互作用,调节5xFAD小鼠中的粉样质斑块积累和陶酸化
bioRxiv : the preprint server for biology
|April 16, 2025
概括
在GABAergic神经元中扰乱大脑的中央昼夜时钟减少了老鼠阿尔茨海默氏症 (AD) 病理,特别是粉样质斑块和陶酸化. 这种效应取决于光暗周期,这表明阿尔茨海默氏症的新疗法目标.
科学领域:
- 神经科学是一个神经科学.
- 时间生物学 时间生物学
- 分子生物学分子生物学
背景情况:
- 循环节律障碍是人类阿尔茨海默氏症 (AD) 的已知后果之一.
- 昼夜干扰作为AD病理学的上游调节者的潜在作用尚不清楚.
- 上神核 (SCN) 中央昼夜时钟是昼夜节律的关键调节器.
研究的目的:
- 研究SCN中央昼夜时钟在调节AD小鼠模型中的粉样蛋白病理学中的作用.
- 为了检查光暗周期如何影响AD病理在中断昼夜节律的背景下.
主要方法:
- 在5xFAD AD小鼠模型中,在SCN GABAergic神经元中产生了基因改造小鼠 (VGAT-BMAL1KO;5xFAD) 具有破坏的BMAL1基因.
- 暴露在12:12光暗 (LD) 周期或持续黑暗 (DD) 条件下的小鼠.
- 评估行为节奏,SCN时钟基因表达,粉样蛋白斑沉积,陶酸化和与粉样蛋白前体蛋白 (APP) 处理相关的基因表达.
主要成果:
- 患有SCN BMAL1 (VGAT-BMAL1KO;5xFAD) 干扰的小鼠表现出严重的行为和分子节律丧失.
- 在LD条件下,这些小鼠与对照小鼠相比显示出粉样蛋白斑块积累和周围斑块 fosforylation的减少.
- 这种病理的减少取决于LD周期,并与参与APP裂变的基因的抑制表达有关.
结论:
- 在SCN昼夜时钟,光暗周期和粉样蛋白病理学调节之间存在相互作用.
- 将中央昼夜时钟与光暗周期脱可能会减少APP裂变和粉样斑块的形成.
- 这些发现挑战了关于昼夜干扰和AD病理之间简单的正反循环的概念.
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