Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease.
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 (Abeta) potentiates mitochondrial, neuronal and synaptic stress. The CypD-deficient cortical mitochondria are resistant to Abeta- and Ca(2+)-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 Abeta- 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 Abeta-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.
Du
Heng
H
Department of Surgery, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, New York 10032, USA.
Guo
Lan
L
Fang
Fang
F
Chen
Doris
D
Sosunov
Alexander A
AA
McKhann
Guy M
GM
Yan
Yilin
Y
Wang
Chunyu
C
Zhang
Hong
H
Molkentin
Jeffery D
JD
Gunn-Moore
Frank J
FJ
Vonsattel
Jean Paul
JP
Arancio
Ottavio
O
Chen
John Xi
JX
Yan
Shi Du
SD
D000544:Alzheimer Disease / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D021983:Cyclophilins / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000502:physiology; D004195:Disease Models, Animal; D006801:Humans; D007858:Learning; D053078:Membrane Potential, Mitochondrial; D008568:Memory; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009474:Neurons / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013569:Synapses / Q000502:physiology; D000097322:Peptidyl-Prolyl Isomerase D
D016229:Amyloid beta-Peptides; D002118:Calcium; D021983:Cyclophilins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; C114456:PPID protein, human; D000097322:Peptidyl-Prolyl Isomerase D