Oxidative stress is closely linked to the pathogenesis of neurodegeneration. Soluble amyloid  (A) oligomers cause cognitive impairment and synaptic dysfunction in Alzheimer disease (AD). However, the relationship between oligomers, oxidative stress, and their localization during disease progression is uncertain. Our previous study demonstrated that mice deficient in cytoplasmic copper/zinc superoxide dismutase (CuZn-SOD, SOD1) have features of drusen formation, a hallmark of agerelated macular degeneration (Imamura, Y., Noda, S., Hashizume, K., Shinoda, K., Yamaguchi, M., Uchiyama, S., Shimizu, T., Mizushima, Y., Shirasawa, T., and Tsubota, K. (2006) Proc. Natl. Acad. Sci. U.S.A. 103, 11282-11287). Amyloid assembly has been implicated as a common mechanism of plaque and drusen formation. Here, we show that Sod1 deficiency in an amyloid precursor protein-overexpressing mouse model (AD mouse, Tg2576) accelerated A oligomerization and memory impairment as compared with control AD mouse and that these phenomena were basically mediated by oxidative damage. The increased plaque and neuronal inflammation were accompanied by the generation of N ⑀ -carboxymethyl lysine in advanced glycation end products, a rapid marker of oxidative damage, induced by Sod1 gene-dependent reduction. The Sod1 deletion also caused Tau phosphorylation and the lower levels of synaptophysin. Furthermore, the levels of SOD1 were significantly decreased in human AD patients rather than non-AD agematched individuals, but mitochondrial SOD (Mn-SOD, SOD2) and extracellular SOD (CuZn-SOD, SOD3) were not. These findings suggest that cytoplasmic superoxide radical plays a critical role in the pathogenesis of AD. Activation of Sod1 may be a therapeutic strategy for the inhibition of AD progression.
Alzheimer disease (AD)3 is characterized by amyloid deposits in senile plaques mainly consisting of 40-and 42-mer amyloid  proteins (A40 and A42) (1, 2). These proteins are produced from amyloid precursor protein (APP) by -and ␥-secretases. A42 plays a more important role in the pathogenesis of AD than A40 because of its greater aggregation propensity and higher neurotoxicity (3). It has been well demonstrated that oxidative stress is a contributing factor to neurodegenerative disease progression (4, 5). A-induced neurotoxicity has been linked to oxidative stress via protein radicalization in vitro (6, 7). Soluble oligomeric assemblies (50ϳ60 kDa; e.g. A-derived diffusible ligand, A * 56, and globulomer) of A rather than insoluble fibrils are believed to inhibit long term potentiation and induce neuronal loss (8, 9).Many defensive systems protect mammals from oxidative stress caused by reactive oxygen species, including superoxide radicals, hydrogen peroxide, hydroxyl radicals, and singlet oxygen. Superoxide dismutase (SOD) is one of the major antioxidant enzymes that catalyzes the conversion of superoxide radicals to hydrogen peroxide (10). SOD consists of three isozymes: copper/zinc SOD (CuZn-SOD, SOD1), which is localized in the cytosol, nucle...
