Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease.

TitleMitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2009
AuthorsYao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, Brinton RDiaz
JournalProc Natl Acad Sci U S A
Date Published2009 Aug 25
KeywordsAlzheimer Disease, Amyloid, Animals, Blotting, Western, Brain, Disease Models, Animal, Electron Transport Complex IV, Female, Hippocampus, Humans, Hydrogen Peroxide, Immunohistochemistry, Lipid Peroxidation, Lipid Peroxides, Mice, Mice, Inbred C57BL, Mice, Inbred Strains, Mice, Transgenic, Mitochondria, Oxidative Stress, Oxygen Consumption, Pyruvate Dehydrogenase (Lipoamide), Time Factors

Mitochondrial dysfunction has been proposed to play a pivotal role in neurodegenerative diseases, including Alzheimer's disease (AD). To address whether mitochondrial dysfunction precedes the development of AD pathology, we conducted mitochondrial functional analyses in female triple transgenic Alzheimer's mice (3xTg-AD) and age-matched nontransgenic (nonTg). Mitochondrial dysfunction in the 3xTg-AD brain was evidenced by decreased mitochondrial respiration and decreased pyruvate dehydrogenase (PDH) protein level and activity as early as 3 months of age. 3xTg-AD mice also exhibited increased oxidative stress as manifested by increased hydrogen peroxide production and lipid peroxidation. Mitochondrial amyloid beta (Abeta) level in the 3xTg-AD mice was significantly increased at 9 months and temporally correlated with increased level of Abeta binding to alcohol dehydrogenase (ABAD). Embryonic neurons derived from 3xTg-AD mouse hippocampus exhibited significantly decreased mitochondrial respiration and increased glycolysis. Results of these analyses indicate that compromised mitochondrial function is evident in embryonic hippocampal neurons, continues unabated in females throughout the reproductive period, and is exacerbated during reproductive senescence. In nontransgenic control mice, oxidative stress was coincident with reproductive senescence and accompanied by a significant decline in mitochondrial function. Reproductive senescence in the 3xTg-AD mouse brain markedly exacerbated mitochondrial dysfunction. Collectively, the data indicate significant mitochondrial dysfunction occurs early in AD pathogenesis in a female AD mouse model. Mitochondrial dysfunction provides a plausible mechanistic rationale for the hypometabolism in brain that precedes AD diagnosis and suggests therapeutic targets for prevention of AD.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID19667196
PubMed Central IDPMC2732886
Grant ListR01 AG032236 / AG / NIA NIH HHS / United States
R01 MH067159 / MH / NIMH NIH HHS / United States
1R01 MH67159-01 / MH / NIMH NIH HHS / United States
1P01AG026572 / AG / NIA NIH HHS / United States
P01 AG026572 / AG / NIA NIH HHS / United States
T32 AG000093 / AG / NIA NIH HHS / United States
T32-AG000093-24/25 / AG / NIA NIH HHS / United States
Faculty Member Reference: 
Roberta Diaz Brinton, Ph.D