Overexpression of SOD-2 reduces hippocampal superoxide and prevents memory deficits in a mouse model of Alzheimer's disease

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 32; pp. 13576 - 13581
• Main Authors: Massaad, Cynthia A, Washington, Taneasha M, Pautler, Robia G, Klann, Eric
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 11.08.2009; National Acad Sciences
• Subjects: Aging - pathology; Alzheimer Disease - enzymology; Alzheimer Disease - pathology; Alzheimer's disease; Alzheimers disease; Amyloid beta-Peptides - metabolism; Amyloids; Animals; Antioxidants; Biological Sciences; Brain; Cognition & reasoning; Disease Models, Animal; Hippocampus - enzymology; Memory; Memory disorders; Memory Disorders - enzymology; Memory Disorders - prevention & control; Mice; Mice, Transgenic; Mutation; Oxidative stress; Plaque, Amyloid - enzymology; Plaque, Amyloid - pathology; Protein precursors; Proteins; Rodents; Superoxide Dismutase - metabolism; Superoxides; Superoxides - metabolism; Transgenic animals
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0902714106

Alzheimer's disease (AD) is a neurodegenerative disease characterized by impaired cognitive function and the deposition of extracellular amyloid plaques and intracellular tangles. Although the proximal cause of AD is not well understood, it is clear that amyloid-β (Aβ) plays a critical role in AD pathology. Recent studies also implicate mitochondrial abnormalities in AD. We investigated this idea by crossing mice that overexpress mitochondrial superoxide dismutase (SOD-2) with the Tg2576 mouse model of AD that overexpresses the human amyloid precursor protein carrying the Swedish mutation (K670N:M671L). We found that overexpression of SOD-2 decreased hippocampal superoxide, prevented AD-related learning and memory deficits, and reduced Aβ plaques. Interestingly, SOD-2 overexpression did not affect the absolute levels of Aβ₁₋₄₀ and Aβ₁₋₄₂, but did significantly reduce the Aβ₁₋₄₂ to Aβ₁₋₄₀ ratio, thereby shifting the balance toward a less amyloidogenic Aβ composition. These findings directly link mitochondrial superoxide to AD pathology and demonstrate the beneficial effects of a mitochondrial anti-oxidant enzyme, hence offering significant therapeutic implications for AD.