Role of endolysosome iron in amyloid-β protein-induced increases in reactive oxygen species,mitochondrial depolarization,and cytotoxicity

Abstract

Background

Alzheimer's disease (AD) is a neurodegenerative disease characterized pathologically by the presence of extracellular plaques containing amyloid-β (Aβ) protein, and intraneuronal accumulations of neurotoxic proteins including Aβ and hyperphosphorylated tau. Also implicated in AD pathophysiology are increased levels of reactive oxygen species (ROS) and iron dyshomeostasis. Ferrous iron (Fe²⁺) controls generation of ROS via Fenton-like reactions and Aβ₄₂ increases levels of intracellular ROS. Endosomes and lysosomes (endolysosomes) are acidic organelles that contain high levels of readily releasable stores of Fe²⁺ and lysosomotropic insults can trigger Fe²⁺ release from endolysosomes, which is sufficient to account for increased levels of cytoplasmic Fe²⁺ and ROS.

Objective

We tested the hypothesis that endolysosome stores of Fe²⁺ were sufficient to control Aβ₄₂-induced increases in mitochondrial Fe²⁺ and ROS, mitochondrial depolarization, and cell death.

Methods

Using SH-SY5Y human neuroblastoma cells, we investigated the effects of Aβ₄₂ (500 nM) and Aβ₄₀ (500 nM) peptides on endolysosome and mitochondrial stress responses.

Results

Aβ₄₂ but not Aβ₄₀ accumulated in and significantly decreased endolysosome Fe²⁺ levels. Further, Aβ₄₂ significantly (1) de-acidified endolysosomes, (2) caused endolysosome damage, (3) caused impaired autophagy, (4) increased levels of cytosolic Fe²⁺ and ROS, (5) increased levels of mitochondrial Fe²⁺ and ROS, (6) decreased mitochondrial membrane potentials, and (7) significantly increased cell death by apoptosis and ferroptosis. These neurotoxic effects were blocked by the endolysosome-specific iron chelator deferoxamine.

Conclusions

Endolysosome stores of Fe²⁺ appear to be important regulators of Aβ₄₂-induced cytotoxicity and targeting these iron stores may lead to new therapeutics against AD-like pathology.