Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease

被引:775
作者
Du, Heng [2 ,3 ]
Guo, Lan [2 ,3 ]
Fang, Fang [2 ,3 ]
Chen, Doris [2 ,3 ]
Sosunov, Alexander A.
McKhann, Guy M.
Yan, Yilin [1 ]
Wang, Chunyu [1 ]
Zhang, Hong [4 ,5 ]
Molkentin, Jeffery D. [6 ]
Gunn-Moore, Frank J. [7 ]
Vonsattel, Jean Paul [4 ]
Arancio, Ottavio [4 ,5 ]
Chen, John Xi [8 ]
Du Yan, Shi [2 ,3 ,4 ,5 ]
机构
[1] Rensselaer Polytech Inst, Dept Biol, Ctr Biotechnol & Interdisciplinary Studies, Troy, NY 12180 USA
[2] Columbia Univ Coll Phys & Surg, Dept Surg, New York, NY 10032 USA
[3] Columbia Univ Coll Phys & Surg, Dept Neurosurg, New York, NY 10032 USA
[4] Columbia Univ Coll Phys & Surg, Dept Pathol, New York, NY 10032 USA
[5] Columbia Univ Coll Phys & Surg, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY 10032 USA
[6] Univ Cincinnati, Childrens Hosp, Med Ctr, Dept Pediat, Cincinnati, OH 45229 USA
[7] Univ St Andrews, Sch Biol, St Andrews KY16 9TS, Fife, Scotland
[8] Cornell Univ, Mem Sloan Kettering Canc Ctr, Dept Neurol, New York, NY 10065 USA
关键词
D O I
10.1038/nm.1868
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
Cyclophilin D (CypD, encoded by Ppif) is an integral part of the mitochondrial permeability transition pore, whose opening leads to cell death. Here we show that interaction of CypD with mitochondrial amyloid-beta protein (A beta) potentiates mitochondrial, neuronal and synaptic stress. The CypD-deficient cortical mitochondria are resistant to A beta- and Ca2+-induced mitochondrial swelling and permeability transition. Additionally, they have an increased calcium buffering capacity and generate fewer mitochondrial reactive oxygen species. Furthermore, the absence of CypD protects neurons from A beta- and oxidative stress-induced cell death. Notably, CypD deficiency substantially improves learning and memory and synaptic function in an Alzheimer's disease mouse model and alleviates A beta-mediated reduction of long-term potentiation. Thus, the CypD-mediated mitochondrial permeability transition pore is directly linked to the cellular and synaptic perturbations observed in the pathogenesis of Alzheimer's disease. Blockade of CypD may be a therapeutic strategy in Alzheimer's disease.
引用
收藏
页码:1097 / 1105
页数:9
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