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

Nat Med. 2008 Oct;14(10):1097-105. doi: 10.1038/nm.1868. Epub 2008 Sep 21.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Amyloid beta-Peptides
  • Mitochondrial Membrane Transport Proteins
  • Reactive Oxygen Species
  • mitochondrial permeability transition pore
  • Cyclophilins
  • PPID protein, human
  • Calcium