The Alzheimer's disease-associated C99 fragment of APP regulates cellular cholesterol trafficking.
The Alzheimer's disease-associated C99 fragment of APP regulates cellular cholesterol trafficking.
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阿尔茨海默氏病与APP相关的C99碎片调节细胞胆固醇的运输。
DOI：
10.15252/embj.2019103791
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发表时间：
2020-10-15
期刊：
影响因子：
--
通讯作者：
Area-Gomez E
中科院分区：
文献类型：
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作者：
Montesinos J;Pera M;Larrea D;Guardia-Laguarta C;Agrawal RR;Velasco KR;Yun TD;Stavrovskaya IG;Xu Y;Koo SY;Snead AM;Sproul AA;Area-Gomez E
胆固醇稳态和淀粉样前体蛋白（APP）裂解之间的联系，以及这种关系如何与阿尔茨海默病（AD）的发病机制，仍然是未知的。细胞胆固醇水平通过质膜（PM）（大多数细胞胆固醇驻留于此）和内质网（ER）（调节胆固醇水平的蛋白质机器驻留于此）之间的串扰来调节。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，该脂质敏感肽可以将PM衍生的胆固醇聚集到ER内的瞬时去污剂抗性膜结构域（DRM）中，也称为胆固醇的ER调节池。当形成时，ER中的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来维持细胞稳态。在这篇文章中，我们提出APP的99个氨基酸C末端片段（C99），当被递送到ER以被γ分泌酶切割时，作为一种脂质敏感肽，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中未裂解的C99的水平增加，疾病的早期表型，通过诱导细胞外胆固醇的内化及其从PM到ER的运输来上调这些瞬时DRM的形成。这些结果表明，C99作为AD中胆固醇紊乱的介体的新作用，可能解释该疾病的早期特征。当递送至ER时，淀粉样前体蛋白APP的C末端BACE1裂解产物作为脂质敏感肽，通过胆固醇的内化和逆行转运促进耐洗涤剂的线粒体相关ER膜（MAM）的形成。
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. When delivered to the ER, the C‐terminal BACE1 cleavage product of amyloid precursor protein APP acts as lipid‐sensing peptide, facilitating formation of detergent‐resistant mitochondria‐associated ER membranes (MAM) via internalization and retrograde transport of cholesterol.