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

      Nature medicine
      Alzheimer Disease, drug therapy, etiology, prevention & control, Amyloid beta-Peptides, metabolism, Animals, Apoptosis, Calcium, Cyclophilins, antagonists & inhibitors, deficiency, physiology, Disease Models, Animal, Humans, Learning, Membrane Potential, Mitochondrial, Memory, Mice, Mitochondria, Mitochondrial Membrane Transport Proteins, Neurons, Reactive Oxygen Species, Synapses

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          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-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.

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