The link between cholesterol homeostasis and cleavage of the amyloid precursor protein (APP), and how this relationship relates to Alzheimer's disease (AD) pathogenesis, is still unknown. Cellular cholesterol levels are regulated through crosstalk between the plasma membrane (PM), where most cellular cholesterol resides, and the endoplasmic reticulum (ER), where the protein machinery that regulates cholesterol levels resides. The intracellular transport of cholesterol from the PM to the ER is believed to be activated by a lipid‐sensing peptide(s) in the ER that can cluster PM‐derived cholesterol into transient detergent‐resistant membrane domains (DRMs) within the ER, also called the ER regulatory pool of cholesterol. When formed, these cholesterol‐rich domains in the ER maintain cellular homeostasis by inducing cholesterol esterification as a mechanism of detoxification while attenuating its de novo synthesis. In this manuscript, we propose that the 99‐aa C‐terminal fragment of APP (C99), when delivered to the ER for cleavage by γ‐secretase, acts as a lipid‐sensing peptide that forms regulatory DRMs in the ER, called mitochondria‐associated ER membranes (MAM). Our data in cellular AD models indicates that increased levels of uncleaved C99 in the ER, an early phenotype of the disease, upregulates the formation of these transient DRMs by inducing the internalization of extracellular cholesterol and its trafficking from the PM to the ER. These results suggest a novel role for C99 as a mediator of cholesterol disturbances in AD, potentially explaining early hallmarks of the disease.

中文翻译：

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APP 中与阿尔茨海默病相关的 C99 片段调节细胞胆固醇运输。


胆固醇稳态与淀粉样前体蛋白 (APP) 裂解之间的联系，以及这种关系与阿尔茨海默病 (AD) 发病机制的关系目前仍不清楚。细胞胆固醇水平是通过质膜（PM）和内质网（ER）之间的串扰来调节的，质膜（PM）是大多数细胞胆固醇所在的地方，内质网（ER）是调节胆固醇水平的蛋白质机制所在的地方。胆固醇从 PM 到 ER 的细胞内转运被认为是由 ER 中的脂质敏感肽激活的，该肽可以将 PM 衍生的胆固醇聚集到 ER 内的瞬时耐去污剂膜域 (DRM) 中，并且称为ER 胆固醇调节库。形成后，内质网中这些富含胆固醇的结构域通过诱导胆固醇酯化作为解毒机制，同时减弱其从头合成，从而维持细胞稳态。在这篇手稿中，我们提出 APP 的 99-aa C 端片段 (C99)，当被递送到 ER 并被 γ-分泌酶裂解时，充当脂质感应肽，在 ER 中形成调节性 DRM，称为线粒体‐相关 ER 膜 (MAM)。我们在细胞 AD 模型中的数据表明，ER（疾病的早期表型）中未切割的 C99 水平增加，通过诱导细胞外胆固醇的内化及其从 PM 到 ER 的运输，上调这些短暂 DRM 的形成。这些结果表明 C99 作为 AD 中胆固醇紊乱的介质具有新的作用，可能解释该疾病的早期特征。