title: SOD1 (copper/zinc superoxide dismutase) deficiency drives amyloid β protein oligomerization and memory loss in mouse model of Alzheimer disease.
abstract: Oxidative stress is closely linked to the pathogenesis of neurodegeneration. Soluble amyloid β (Aβ) 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 age-related 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 Aβ 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(ε)-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 age-matched 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.
authors.affiliation: Molecular Gerontology, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0015, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Murakami
authors.forename: Nakaba
authors.initials: N
authors.lastname: Murata
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Noda
authors.forename: Shoichi
authors.initials: S
authors.lastname: Tahara
authors.forename: Takao
authors.initials: T
authors.lastname: Kaneko
authors.forename: Noriaki
authors.initials: N
authors.lastname: Kinoshita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hatsuta
authors.forename: Shigeo
authors.initials: S
authors.lastname: Murayama
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Barnham
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Irie
authors.forename: Takuji
authors.initials: T
authors.lastname: Shirasawa
authors.forename: Takahiko
authors.initials: T
authors.lastname: Shimizu
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000235:genetics; D017127:Glycation End Products, Advanced / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008239:Lysine / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D055503:Protein Multimerization; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D013481:Superoxides / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D017127:Glycation End Products, Advanced; C000606290:SOD1 protein, human; D013481:Superoxides; C048496:N(6)-carboxymethyllysine; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D008239:Lysine
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