Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease Journal Article
| Authors: | Du, H.; Guo, L.; Fang, F.; Chen, D.; A Sosunov, A.; M McKhann, G.; Yan, Y.; Wang, C.; Zhang, H.; Molkentin, J. D.; Gunn Moore, F. J.; Vonsattel, J. P.; Arancio, O.; Chen, J. X.; Yan, S. D. |
| Article Title: | Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease |
| 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 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 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. © 2008 Nature Publishing Group. |
| Keywords: | controlled study; human tissue; nonhuman; mouse; animals; mice; apoptosis; oxygen; animal experiment; animal model; calcium; protein interaction; neurons; reactive oxygen species; stress; memory; disease models, animal; mitochondria; mitochondrion; membrane potential, mitochondrial; alzheimer disease; cell membrane permeability; learning; synapses; amyloid beta-protein; synapse; amyloid beta protein; cyclophilin d; cyclophilins; long term potentiation; mitochondrial membrane transport proteins |
| Journal Title: | Nature Medicine |
| Volume: | 14 |
| Issue: | 10 |
| ISSN: | 1078-8956 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2008-10-01 |
| Start Page: | 1097 |
| End Page: | 1105 |
| Language: | English |
| DOI: | 10.1038/nm.1868 |
| PUBMED: | 18806802 |
| PROVIDER: | scopus |
| PMCID: | PMC2789841 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 144" - "Export Date: 17 November 2011" - "CODEN: NAMEF" - "Source: Scopus" |
