Brain Metabolite, Myo-inositol, Inhibits Catalase Activity: A Mechanism of the Distortion of the Antioxidant Defense System in Alzheimer's disease.

A strong correlation between brain metabolite accumulation and oxidative stress has been observed in Alzheimer's disease (AD) patients. There are two central hypotheses for this correlation: (i) coaccumulation of toxic amyloid-β and Myo-inositol (MI), a significant brain metabolite, during presymptomatic stages of AD, and (ii) enhanced expression of MI transporter in brain cells during oxidative stress-induced volume changes in the brain. Identifying specific interactive effects of MI with cellular antioxidant enzymes would represent an essential step in understanding the oxidative stress-induced AD pathogenicity. This study demonstrated that MI inhibits catalase, an essential antioxidant enzyme primarily inefficient in AD, by decreasing its k cat (turnover number) and increasing K m (Michaelis-Menten constant) values. This inhibition of catalase by MI under in vivo studies increased cellular H 2 O 2 levels, leading to decreased cell viability. Furthermore, MI induces distortion of the active heme center with an overall loss of structure and stability of catalase. MI also alters distances of the vital active site and substrate channel residues of catalase. The present study provides evidence for the involvement of MI in the inactivation of the antioxidant defense system during oxidative stress-induced pathogenesis of AD. Regulation of MI levels, during early presymptomatic stages of AD, might serve as a potential early-on therapeutic strategy for this disease.