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

Topic: Disease mechanisms in lab and animal studies

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.

Key findings

• 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.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/nm.1868
• PubMed: 18806802
• Original source →

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@article{du2008-18806802,
  author  = {Du, H. and Guo, L. and Fang, F. and Chen, D. and Sosunov, A. A. and McKhann, G. M. and Yan, Y. and Wang, C. and others},
  title   = {{Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease}},
  journal = {Nature medicine},
  year    = {2008},
  doi     = {10.1038/nm.1868},
  pmid    = {18806802},
  url     = {https://doi.org/10.1038/nm.1868}
}

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