Cyclophilin D deficiency improves mitochondrial function and learning/memory in aging Alzheimer disease mouse model.

Abstract

Mitochondrial stress is one of the early features of Alzheimer disease (AD). Mitochondrial Aβ has been linked to mitochondrial toxicity. Our recent study demonstrated that cyclophilin D (CypD) mediated mitochondrial permeability transition pore (mPTP) is an important mechanism for neuronal and synaptic stress induced by both Aβ and oxidative stress. In transgenic AD-type mice overexpressing mutant amyloid precursor protein (APP) and Aβ (mAPP), CypD deficiency improves mitochondrial and synaptic function and learning/memory up to 12 months old. Here we provide evidence of the protective effects of CypD deficiency in aged AD mice (22-24 months). Cyp D deficient mAPP mice demonstrate less calcium-induced mitochondrial swelling, increased mitochondrial calcium uptake capacity, preserved mitochondrial respiratory function and improved spatial learning/memory even in old age (known to be the age for late stage AD pathology and synaptic dysfunction). These data demonstrate that abrogation of CypD results in persistent life-long protection against Aβ toxicity in an Alzheimer's disease mouse model, thereby suggesting that blockade of CypD may be of benefit for Alzheimer disease treatment.

• Authors: Heng Du, Lan Guo, Wensheng Zhang, Monika Rydzewska, Shidu Yan
• Journal: Neurobiology of aging (Neurobiol Aging) Vol. 32 Issue 3 Pg. 398-406 (Mar 2011) ISSN: 1558-1497 [Electronic] United States
• PMID: 19362755 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2009 Elsevier Inc. All rights reserved.

Chemical References

• Amyloid beta-Protein Precursor
• Cyclophilin D
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• PPIF protein, mouse
• Electron Transport Complex IV
• Cyclophilins
• Calcium

Topics

• Aging
• Alzheimer Disease (complications, genetics)
• Amyloid beta-Protein Precursor (genetics)
• Analysis of Variance
• Animals
• Brain (metabolism)
• Calcium (metabolism)
• Cyclophilin D
• Cyclophilins (deficiency, metabolism)
• Disease Models, Animal
• Electron Transport Complex IV (metabolism)
• Humans
• Learning Disabilities (etiology, pathology)
• Maze Learning (physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Mitochondria (physiology)
• Mitochondrial Membrane Transport Proteins (metabolism)
• Mitochondrial Permeability Transition Pore
• Mutation (genetics)
• Protein Transport (genetics)