Mitochondrial oxidative stress causes hyperphosphorylation of tau

Journal article

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 beta-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.

Authors: Melov, S; Adlard, P; Morten, K; Johnson, F; Golden, T

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Public Library of Science
• Journal: PLoS ONE
• Volume: 2
• Issue: 6
• Pages: e536
• Publication date: 2007-06-20
• Acceptance date: 2007-05-16
• DOI: 10.1371/journal.pone.0000536
• EISSN: 1932-6203
• Language: English
• Keywords: Oxidative Stress; Immunoenzyme Techniques; Reactive Oxygen Species; Mice, Inbred C57BL; Male; tau Proteins; SBTMR; Antioxidants; Female; Mice, Knockout; Metals; Immunoprecipitation; Animals; Blotting, Western; Superoxide Dismutase; Mitochondria; Spectrometry, Mass, Electrospray Ionization; Plaque, Amyloid; Phosphorylation; Mice