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Synthesized Aβ42 Caused Intracellular Oxidative Damage, Leading to Cell Death, via Lysosome Rupture
Yuki Oku1, Kazuma Murakami2,3, Kazuhiro Irie2,3
1Graduate School of Advanced Integrated Studies, Kyoto University.
Abstract:
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).
Insights
Toxic amyloid-beta (Aβ) oligomers accumulate in lysosomes, increasing reactive oxygen species (ROS) and causing cell death via lysosomal membrane permeabilization (LMP). Targeting lysosomal ROS and LMP may prevent Alzheimer
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Neuronal accumulation of amyloid-beta peptide (Aβ) is linked to Alzheimer's disease (AD) pathogenesis.
- Intracellular Aβ42 accumulation occurs early in AD, but its role in cell death mechanisms is unclear.
Purpose of the Study:
- To elucidate the cellular mechanism by which intracellular Aβ42 leads to neuronal cell death.
- To investigate the role of Aβ42 oligomerization and lysosomal dysfunction in AD.
Main Methods:
- Utilized chemically synthesized Aβ42 variants with differing oligomerization tendencies.
- Assessed Aβ42 localization, ROS production, and lysosomal membrane permeabilization (LMP) using markers like EGFP-Galectin-3 and LAMP1.
- Investigated the effect of interventions like peroxiredoxin 1 overexpression and U18866A treatment.
Main Results:
- Aβ42 variant (E22P), prone to oligomerization, accumulated in lysosomes, increased ROS, and induced cell death.
- Aβ42 variant (E22V), incapable of oligomerization, did not cause cell death.
- Oligomerized Aβ42 accumulation triggered LMP, which was attenuated by interventions stabilizing lysosomal membranes.
Conclusions:
- Lysosomal generation of ROS by toxic Aβ conformers causes cell death through LMP.
- These findings highlight lysosomal dysfunction as a key mechanism in Aβ-induced neurodegeneration.
- Targeting lysosomal ROS and LMP presents a potential therapeutic strategy for Alzheimer's disease prevention.