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. Simon Melov1*, Paul A. Adlard2, Karl Morten1, Felicity Johnson1, Tamara R. Golden1, Doug Hinerfeld1, Birgit Schilling1, Christine Mavros2, Colin L. Masters2, Irene Volitakis2, Qiao-Xin Li2, Katrina Laughton2, Alan Hubbard3, Robert A. Cherny2, Brad Gibson1, Ashley I. Bush2,4* 1 Buck Institute for Age Research, Novato, California, United States of America, 2 Mental Health Research Institute of Victoria, and Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia, 3 School of Public Health, EHS/Biostatistics, University of California Berkeley, Berkeley, California, United States of America, 4 Department of Psychiatry, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America (Journal article originally published in PLoS. Open Access.)