Upregulated function of mitochondria-associated ER membranes in Alzheimer disease

被引:491
作者
Area-Gomez, Estela [2 ]
Castillo, Maria Del Carmen Lara [2 ]
Tambini, Marc D. [1 ]
Guardia-Laguarta, Cristina [3 ]
de Groof, Ad J. C. [2 ,4 ]
Madra, Moneek [5 ]
Ikenouchi, Junichi
Umeda, Masato [6 ]
Bird, Thomas D. [7 ,8 ]
Sturley, Stephen L. [5 ]
Schon, Eric A. [2 ,9 ]
机构
[1] Columbia Univ, Med Ctr, Dept Cellular Mol & Biophys Studies, New York, NY 10032 USA
[2] Columbia Univ, Med Ctr, Dept Neurol, New York, NY 10032 USA
[3] Columbia Univ, Med Ctr, Dept Pathol & Cell Biol, New York, NY 10032 USA
[4] Radboud Univ Nijmegen, NCMLS, Dept Cell Biol, NL-6525 ED Nijmegen, Netherlands
[5] Columbia Univ, Med Ctr, Dept Pediat, New York, NY 10032 USA
[6] Kyoto Univ, Dept Synthet Chem & Biol Chem, Kyoto, Japan
[7] Univ Washington, Div Neurogenet, Seattle, WA 98195 USA
[8] VA Med Ctr, Geriatr Res Ctr, Seattle, WA USA
[9] Columbia Univ, Med Ctr, Dept Genet & Dev, New York, NY 10032 USA
基金
日本科学技术振兴机构;
关键词
APP; cholesterol; MAM; phospholipids; presenilin; AMYLOID PRECURSOR PROTEIN; GAMMA-SECRETASE ACTIVITY; BLOOD MONONUCLEAR-CELLS; C-TERMINAL FRAGMENT; ENDOPLASMIC-RETICULUM; LIPID RAFTS; A-BETA; SUBCELLULAR-LOCALIZATION; INTRACELLULAR DOMAIN; SKIN FIBROBLASTS;
D O I
10.1038/emboj.2012.202
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Alzheimer disease (AD) is associated with aberrant processing of the amyloid precursor protein (APP) by gamma-secretase, via an unknown mechanism. We recently showed that presenilin-1 and -2, the catalytic components of gamma-secretase, and gamma-secretase activity itself, are highly enriched in a subcompartment of the endoplasmic reticulum (ER) that is physically and biochemically connected to mitochondria, called mitochondria-associated ER membranes (MAMs). We now show that MAM function and ER-mitochondrial communication-as measured by cholesteryl ester and phospholipid synthesis, respectively-are increased significantly in presenilin-mutant cells and in fibroblasts from patients with both the familial and sporadic forms of AD. We also show that MAM is an intracellular detergent-resistant lipid raft (LR)-like domain, consistent with the known presence of presenilins and gamma-secretase activity in rafts. These findings may help explain not only the aberrant APP processing but also a number of other biochemical features of AD, including altered lipid metabolism and calcium homeostasis. We propose that upregulated MAM function at the ER-mitochondrial interface, and increased cross-talk between these two organelles, may play a hitherto unrecognized role in the pathogenesis of AD. The EMBO Journal (2012) 31, 4106-4123. doi: 10.1038/emboj.2012.202; Published online 14 August 2012
引用
收藏
页码:4106 / 4123
页数:18
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