Cytoplasmic superoxide radical: a possible contributing factor to intracellular Aβ oligomerization in Alzheimer disease

Abstract

Soluble amyloid β (Aβ) oligomers cause memory loss and synaptic dysfunction in Alzheimer disease (AD). Despite intensive studies on Aβ assembly in vitro and in vivo, the localization and cellular mechanism of Aβ oligomerization are not fully understood. Previously, we demonstrated that cytoplasmic superoxide radicals contribute to drusen deposition, a hallmark of age-related macular degeneration as well as other geriatric diseases (fatty liver, skin thinning, and osteoporosis). Using a transgenic mouse model of AD, we recently clarified the role of cytoplasmic oxidative stress in cognitive impairment and oligomer formation. Moreover, we also found that these phenomena were associated with neuroinflammation, tau phosphorylation, and synaptic loss. Notably, studies using human brains support the involvement of cytoplasmic superoxide radicals in AD pathology. In this addendum to Murakami et al. (JBC 2011), we discuss and comment on intracellular Aβ oligomer formation and the possible therapeutic effects of intracellular redox state modulators.

Keywords: Alzheimer’s disease; SOD; amyloid β; memory loss; oligomer; oxidative stress; superoxide radical.

Figure 1. An increase of Aβ oligomer by Sod1 deletion in Alzheimer mice. (A) ELISA analysis of 82E1-specific oligomers using the TBS-soluble fraction of brains of mice (n = 5~7 per genotype) of the indicated genotypes and age. In ELISA for Aβ oligomers (Immuno Biochemical Laboratories: IBL, Gunma, Japan), the same N-terminal Aβ antibody (82E1) is used both for antigen capture and detection. In the younger ages (6−8-mo-old), the level of only Aβ oligomers was significantly increased in hAPP/Sod1^-/- as compared with the hAPP/Sod1^+/+ mice, but not Aβ42 or Aβ40 (ref. 15). On the other hand, older (15−17-mo-old) hAPP/Sod1^-/- showed a significant elevation of Aβ oligomers as well as Aβ42 and Aβ40 (ref. 15) as compared with the hAPP/Sod1^+/+ mice. These data are rearrangement of the previous work (ref. 15). (B) Distribution of Aβ aggregates by western blotting of mice (n = 4~5 per genotype) of the indicated genotypes and age. The detailed procedure was described previously (ref. 15). In brief, Tris buffered saline (TBS)-soluble fractions (2 µg/µL) were subjected to western blotting using 10–20% Tricine gel (Invitrogen) and transferred to a PVDF membrane (0.2 μm pore size, Bio-rad). Anti-Aβ antibody (6E10, 1:1,000, Signet) was used for Aβ detection. Overexposed bands corresponding to the hexamer (arrows: ~30 kDa) were used for relative quantification. left: 6−8-mo-old, right: 15−17-mo-old. *p < 0.05 vs. hAPP/Sod1^+/+, mean ± s.e.m.