Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease.
Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease.
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DOI：
10.15252/embj.201796797
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发表时间：
2017-11-15
期刊：
影响因子：
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通讯作者：
Area-Gomez E
中科院分区：
文献类型：
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作者：
Pera M;Larrea D;Guardia-Laguarta C;Montesinos J;Velasco KR;Agrawal RR;Xu Y;Chan RB;Di Paolo G;Mehler MF;Perumal GS;Macaluso FP;Freyberg ZZ;Acin-Perez R;Enriquez JA;Schon EA;Area-Gomez E
在与阿尔茨海默病（AD）相关的淀粉样蛋白生成途径中，淀粉样蛋白前体蛋白（APP）被β分泌酶裂解生成99‐aa C‐末端片段（C99），然后被γ分泌酶裂解生成老年斑中发现的β‐淀粉样蛋白（a β）。在之前的报道中，我们和其他人已经表明γ -分泌酶活性在线粒体相关内质网（ER）膜（MAM）中富集，并且在AD中ER -线粒体连通性和MAM功能上调。我们现在发现，C99除了定位于核内体之外，也可以在MAM中发现，在那里它通常被γ -分泌酶快速处理。然而，在AD细胞模型中，MAM区域未加工的C99浓度增加，导致鞘脂代谢升高，MAM和线粒体膜的脂质组成改变。反过来，线粒体膜组成的这种变化干扰了线粒体呼吸超复合体的正常组装和活性，从而可能导致AD特征的生物能量缺陷。
In the amyloidogenic pathway associated with Alzheimer disease (AD), the amyloid precursor protein (APP) is cleaved by β‐secretase to generate a 99‐aa C‐terminal fragment (C99) that is then cleaved by γ‐secretase to generate the β‐amyloid (Aβ) found in senile plaques. In previous reports, we and others have shown that γ‐secretase activity is enriched in mitochondria‐associated endoplasmic reticulum (ER) membranes (MAM) and that ER–mitochondrial connectivity and MAM function are upregulated in AD. We now show that C99, in addition to its localization in endosomes, can also be found in MAM, where it is normally processed rapidly by γ‐secretase. In cell models of AD, however, the concentration of unprocessed C99 increases in MAM regions, resulting in elevated sphingolipid turnover and an altered lipid composition of both MAM and mitochondrial membranes. In turn, this change in mitochondrial membrane composition interferes with the proper assembly and activity of mitochondrial respiratory supercomplexes, thereby likely contributing to the bioenergetic defects characteristic of AD.