Synthesized Aβ42 Caused Intracellular Oxidative Damage, Leading to Cell Death, via Lysosome Rupture.

Neuronal cellular accumulation of amyloid beta peptide (Aβ) has been implicated in the pathogenesis of Alzheimer's disease (AD). Intracellular accumulation of Aβ42, a toxic form of Aβ, was observed as an early event in AD patients. However, its contribution and the cellular mechanism of cell death remained unclear. We herein revealed the mechanism by which Aβ42 incorporated into cells leads to cell death by using chemically synthesized Aβ42 variants. The Aβ42 variant Aβ42 (E22P) which has an increased tendency to oligomerize, accumulated in lysosomes at an earlier stage than wild-type Aβ42, leading to higher ROS production and lysosomal membrane oxidation, and resulting in cell death. On the other hand, Aβ42 (E22V), which is incapable of oligomerization, did not accumulate in cells or affect the cell viability. Moreover, intracellular localization of EGFP-Galectin-3, a β-galactoside binding lectin, showed that accumulation of oligomerized Aβ42 in lysosomes caused lysosomal membrane permeabilization (LMP). Overexpression of lysosome-localized LAMP1-fused peroxiredoxin 1 and treatment with U18866A, an inhibitor of cholesterol export from lysosomes that causes an increase in lysosomal membrane stability, attenuated Aβ42-mediated LMP and cell death. Our findings show that lysosomal ROS generation by toxic conformer of Aβ led to cell death via LMP, and suggest that these events are potential targets for AD prevention.Key words: Amyloid-beta (Aβ), Cell death, Lysosome, Lysosomal membrane permeabilization, Reactive oxygen species (ROS).