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铁对溶酶体干扰的反应:通往阿尔茨海默病的新途径

Jack T Rogers¹, Catherine M Cahill¹

¹Neurochemistry Laboratory, Massachusetts General Hospital (East), and Harvard Medical School, Charlestown, MA, USA.

Journal of Alzheimer's disease : JAD

|October 2, 2023

概括

家族性阿尔茨海默氏症突变通过影响粉样蛋白前体蛋白 (AβPP) 水平和溶酶体功能,损害了大脑的铁加工. 这可能导致神经退行,但铁反应元件 (IRE) 提供了一个潜在的适应机制.

科学领域:

神经科学是一个神经科学.
分子生物学分子生物学
生物化学生物化学

背景情况:

在粉样β蛋白前体 (AβPP) 中的家族性阿尔茨海默病 (fAD) 突变与大脑AβPP C-终端片段 (CTF) 水平的改变有关.
由AβPP CTFs抑制 lysosomal v-ATPase,破坏了内分泌体通路的酸化,可能导致大脑缺铁和线粒体功能障碍.

研究的目的:

为了研究铁反应元素 (IRE) 在 AβPP mRNA调节中的作用,在fAD相关的铁异常常态的背景下.
探索AβPP转化,铁平衡和神经保护之间的相互作用.

主要方法:

与 lysosomal v-ATPase活性相关的 AβPP C-终端片段 (CTF) 水平的分析.
通过其5'非转化区域 (UTR) IRE检查AβPP的依赖铁的转化调制.
评估转激素受体表达作为细胞铁状况指标.

主要成果:

fAD突变增强了AβPP CTF水平,抑制了 lysosomal v-ATPase,并破坏了内分泌体酸化.
降低生物可用铁 (Fe-II) 降低了依赖IRE的AβPP转化和APP-CTFβ水平,这表明一种适应性反应可以恢复铁的平衡.
观察到转激素受体水平增加,表明细胞缺铁.

结论:

破坏的内分泌体酸性化和铁双体平衡与fAD病变发生有关.
IRE介导的AβPP的转化控制代表了一种反机制,以适应性地管理细胞铁水平.
溶性AβPPα (sAβPPα) 在健康个体的铁运输和AβPP转化调节中起着神经保护作用.

关键词:

5未翻译的地区阿尔茨海默氏症是阿尔茨海默氏症的一种疾病.在C端的碎片.氨基酸β蛋白质前体的前体.铁是铁,铁是铁,铁是铁.铁的平衡是铁的平衡.铁调节蛋白是铁的调节蛋白.铁是一种响应性元素.溶解体是溶解体的组成部分.

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