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-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.

• Authors: Heng Du, Lan Guo, Fang Fang, Doris Chen, Alexander A Sosunov, Guy M McKhann, Yilin Yan, Chunyu Wang, Hong Zhang, Jeffery D Molkentin, Frank J Gunn-Moore, Jean Paul Vonsattel, Ottavio Arancio, John Xi Chen, Shi Du Yan
• Journal: Nature medicine (Nat Med) Vol. 14 Issue 10 Pg. 1097-105 (Oct 2008) ISSN: 1546-170X [Electronic] United States
• PMID: 18806802 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• Reactive Oxygen Species
• Cyclophilins
• PPID protein, human
• Calcium

Topics

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