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

H Du, L Guo, F Fang, D Chen, A Sosunov, G McKhann, Y Yan, C Wang, H Zhang, J Molkentin, Francis James Gunn-Moore, JP Vonsattel, O Arancio, JX Chen, SD Yan

Research output: Contribution to journalArticlepeer-review

670 Citations (Scopus)

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 (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.

Original languageEnglish
Pages (from-to)1097-1105
Number of pages9
JournalNature Medicine
Volume14
Issue number10
DOIs
Publication statusPublished - Oct 2008

Keywords

  • PERMEABILITY TRANSITION PORE
  • AMYLOID PRECURSOR PROTEIN
  • LONG-TERM POTENTIATION
  • MANGANESE SUPEROXIDE-DISMUTASE
  • ADENINE-NUCLEOTIDE TRANSLOCASE
  • SURFACE-PLASMON RESONANCE
  • FOCAL CEREBRAL-ISCHEMIA
  • FREE-RADICAL GENERATION
  • CYTOCHROME-C-OXIDASE
  • A-BETA

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