Mitochondrial Dysfunction and Alzheimers Disease
Xi Chen, David Stern and Shi Du Yan
Affiliation: Department of Pathology, Surgery, and Taub Institute for Research on Alzheimer's Disease and the Ageing Brain, College of Physician&Surgeons of Columbia University, 650 West 168th Street, New York, NY 10032, USA.
Keywords: cytochrome c oxidase (COX), reactive oxygen species (ROS), AD-specific mtDNA variants, amyloid precursor protein, ABAD interaction
Mitochondrial dysfunction has been implicated in causing metabolic abnormalities in Alzheimers disease (AD). The searches for mitochondrial DNA variants associated with AD susceptibility have generated conflicting results. The age-related accumulation of somatic mitochondrial DNA deletion has been suggested to play a pathogenic role in the development of AD. Recent studies have demonstrated that amyloid-beta peptide (Aβ) progressively accumulates in mitochndrial matrix, as demonstrated in both transgenic mice over-expressing mutant amyloid precursor protein (APP) and autopsy brain from AD patients. Aβ-mediated mitochondrial stress was evidenced by impaired oxygen consumption and decreased respiratory chain complexes III and IV activities in brains from AD patients and AD-type transgenic mouse model. Furthermore, our studies indicated that interaction of intramitochondrial Aβ with a mitochondrial enzyme, amyloid binding alcohol dehydrogenase (ABAD), inhibits its enzyme activity, enhances generation of reactive oxygen species (ROS), impairs energy metabolism, and exaggerates Aβ-induced spatial learning/memory deficits and neuropathological changes in transgenic AD-type mouse model. Interception of ABAD-Aβ interaction may be a potential therapeutic strategy for Alzheimers disease.
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