Mitochondrial Oxidative Stress Causes Hyperphosphorylation of Tau

Simon Melov,Brad Gibson,Karl Morten,Colin L Masters,Qiao-Xin Li,Robert A Cherny,Doug Hinerfeld,Birgit Schilling,Irene Volitakis,Alan Hubbard,Felicity Johnson,Ashley I Bush,Katrina Laughton,Tamara R Golden,Christine Mavros,Paul A Adlard,Joseph El Khoury

doi:10.1371/journal.pone.0000536

Abstract

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.

Highlights

Mitochondria are a main source of potentially pathogenic reactive oxygen species (ROS) such as superoxide, in highly metabolically active organs such as the brain and heart [1,2,3]
To test whether mitochondrial oxidative stress causes hyperphosphorylation of tau, we studied sod2 null mice that were treated with a catalytic antioxidant (EUK189)
Treating sod2 null mice with a high dose of EUK189 (30 mg/kg) improves survival, behavioral abnormalities, and transcriptional responses associated with oxidative stress, in conjunction with increasing activities of mitochondrial enzymes that are sensitive to mitochondrial oxidative stress [2,14], as well as preventing spongiform neuropathology

Summary

Introduction

Mitochondria are a main source of potentially pathogenic reactive oxygen species (ROS) such as superoxide, in highly metabolically active organs such as the brain and heart [1,2,3]. The resulting phenotypes include neonatal or embryonic lethality [5,6], cardiomyopathy [5,6], hemolytic anemia [7,8], seizures [6], increased incidence of cancer [9], genomic instability [10], mitochondrial biochemical defects [11,12], spongiform encephalopathy [3], optic neuropathy [4], movement disorders [3,6] and neurodegeneration [12] These phenotypes arise due to endogenous oxidative stress and several antioxidant interventions have been applied to the sod nullizygous mouse model [2,3,13]. Some of these interventions have striking efficacy in preventing cardiomyopathy, extending lifespan, preventing spongiform encephalopathy [2,3], reducing anemia [7], increasing mitochondrial enzyme activity, reducing neurodegeneration and attenuating gene expression characteristic of mitochondrially mediated spongiform encephalopathy [12,14]

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