Mitochondrial superoxide contributes to blood flow and axonal transport deficits in the Tg2576 mouse model of Alzheimer's disease.
BACKGROUND
Alzheimer's disease (AD) is a neurodegenerative disease characterized by the progressive decline in cognitive functions and the deposition of aggregated amyloid beta (Abeta) into senile plaques and the protein tau into tangles. In addition, a general state of oxidation has long been known to be a major hallmark of the disease. What is not known however, are the mechanisms by which oxidative stress contributes to the pathology of AD.


RESULTS
In the current study, we used a mouse model of AD and genetically boosted its ability to quench free radicals of specific mitochondrial origin. We found that such manipulation conferred to the AD mice protection against vascular as well as neuronal deficits that typically affect them. We also found that the vascular deficits are improved via antioxidant modulation of the endothelial nitric oxide synthase, an enzyme primarily responsible for the production of nitric oxide, while neuronal deficits are improved via modulation of the phosphorylation status of the protein tau, which is a neuronal cytoskeletal stabilizer.


CONCLUSIONS
These findings directly link free radicals of specific mitochondrial origin to AD-associated vascular and neuronal pathology.
Massaad
Cynthia A
CA
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, United States of America.
Amin
Samir K
SK
Hu
Lingyun
L
Mei
Yuan
Y
Klann
Eric
E
Pautler
Robia G
RG
D000544:Alzheimer Disease / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D002560:Cerebrovascular Circulation / Q000502:physiology*; D004195:Disease Models, Animal; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism
D016875:tau Proteins; D013481:Superoxides; D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase