PLoS ONE. 2007 Jun 20;2:e536.
Mitochondrial oxidative stress causes hyperphosphorylation of tau.
Melov S, Adlard PA, Morten K, Johnson F, Golden TR, Hinerfeld D,
Schilling B, Mavros C, Masters CL, Volitakis I, Li QX, Laughton K,
Hubbard A, Cherny RA, Gibson B, Bush AI.
Buck Institute for Age Research, Novato, California, United States of
America.
Age-related neurodegenerative disease has been mechanistically linked
with mitochondrial dysfunction via damage from reactive oxygen species
produced within the cell. We determined whether increased
mitochondrial oxidative stress could modulate or regulate two of the
key neurochemical hallmarks of Alzheimer's disease (AD): tau
phosphorylation, and ss-amyloid deposition. Mice lacking superoxide
dismutase 2 (SOD2) die within the first week of life, and develop a
complex heterogeneous phenotype arising from mitochondrial dysfunction
and oxidative stress. Treatment of these mice with catalytic
antioxidants increases their lifespan and rescues the peripheral
phenotypes, while uncovering central nervous system pathology. We
examined sod2 null mice differentially treated with high and low doses
of a catalytic antioxidant and observed striking elevations in the
levels of tau phosphorylation (at Ser-396 and other phospho-epitopes
of tau) in the low-dose antioxidant treated mice at AD-associated
residues. This hyperphosphorylation of tau was prevented with an
increased dose of the antioxidant, previously reported to be
sufficient to prevent neuropathology. We then genetically combined a
well-characterized mouse model of AD (Tg2576) with heterozygous sod2
knockout mice to study the interactions between mitochondrial
oxidative stress and cerebral Ass load. We found that mitochondrial
SOD2 deficiency exacerbates amyloid burden and significantly reduces
metal levels in the brain, while increasing levels of Ser-396
phosphorylated tau. These findings mechanistically link mitochondrial
oxidative stress with the pathological features of AD.
PMID: 17579710 [PubMed - in process]
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