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Article
Nature Medicine 14, 1097 - 1105 (2008)
Published online: 21 September 2008 | doi:10.1038/nm.1868
Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease
Heng Du1, Lan Guo1, Fang Fang1, Doris Chen1, Alexander A Sosunov2, Guy M McKhann2, Yilin Yan3, Chunyu Wang3, Hong Zhang4,5, Jeffery D Molkentin6, Frank J Gunn-Moore7, Jean Paul Vonsattel4, Ottavio Arancio4,5, John Xi Chen8 & Shi Du Yan1,4,5
Abstract
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-
protein (A) potentiates mitochondrial, neuronal and synaptic stress. The CypD-deficient cortical mitochondria are resistant to A- 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- 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-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.
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