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

Nature Medicine volume 14, pages 1097–1105 (2008)Cite this article

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-β protein (Aβ) potentiates mitochondrial, neuronal and synaptic stress. The CypD-deficient cortical mitochondria are resistant to Aβ- 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 Aβ- 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 Aβ-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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Figure 1: Interaction of CypD with Aβ.
Figure 2: Colocalization of CypD and Aβ in mitochondria.
Figure 3: Effect of CypD deficiency on mitochondrial function in mAPP mice.
Figure 4: Effect of CypD deficiency on ROS production and mitochondrial function in mAPP mice.
Figure 5: Aβ- and H2O2-induced mitochondrial and neuronal dysfunction in cultured neurons.
Figure 6: Effect of CypD deficiency on spatial learning and memory and on Aβ-induced LTP.

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Acknowledgements

This work was supported by the US Public Health Service Commissioned Corps (PO1 AG17490, PO50 AG08702) and the Alzheimer's Association. We thank S. Katz for assistance with performing the behavioral experiments.

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Authors and Affiliations

  1. Departments of Surgery, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, 10032, New York, USA

    Heng Du, Lan Guo, Fang Fang, Doris Chen & Shi Du Yan

  2. Neurosurgery, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, 10032, New York, USA

    Alexander A Sosunov & Guy M McKhann

  3. Biology Department, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, 12180-3590, New York, USA

    Yilin Yan & Chunyu Wang

  4. Department of Pathology, the Aging Brain, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, 10032, New York, USA

    Hong Zhang, Jean Paul Vonsattel, Ottavio Arancio & Shi Du Yan

  5. Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, 10032, New York, USA

    Hong Zhang, Ottavio Arancio & Shi Du Yan

  6. Department of Pediatrics, University of Cincinnati, Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, 45229, Ohio, USA

    Jeffery D Molkentin

  7. School of Biology, 79 North Street, University of St. Andrews, St. Andrews, KY16 9TS, Scotland

    Frank J Gunn-Moore

  8. Department of Neurology, Memorial Sloan-Kettering Cancer Center, Cornell University, 1275 York Avenue, New York, 10065, New York, USA

    John Xi Chen

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Contributions

H.D. designed and did experiments and assisted with the preparation of the manuscript. L.G. contributed to the study of in vitro cultured neurons. F.F. did quantitative real-time PCR experiments. L.G. and D.C. performed genotyping of transgenic mice. A.A.S. and G.M.M. conducted electron microscopy studies. Y.Y. and C.W. performed surface plasmon resonance experiments. F.J.G.-M. provided some suggestions. J.D.M. provided CypD-knockout mice. H.Z. and O.A. performed LTP experiments. J.P.V. provided information of human brain tissues. J.X.C. provided suggestions for the experimental design and assisted with the preparation of manuscript. S.D.Y. initiated, directed and supervised the research, designed and assisted experiments, analyzed data, developed the concept and wrote the manuscript.

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Correspondence to Shi Du Yan.

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Du, H., Guo, L., Fang, F. et al. Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease. Nat Med 14, 1097–1105 (2008). https://doi.org/10.1038/nm.1868

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