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

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 (Fe 2+ ) controls generation of ROS via Fenton-like reactions and Aβ 42 increases levels of intracellular ROS. Endosomes and lysosomes (endolysosomes) are acidic organelles that contain high levels of readily releasable stores of Fe 2+ and lysosomotropic insults can trigger Fe 2+ release from endolysosomes, which is sufficient to account for increased levels of cytoplasmic Fe 2+ and ROS. Objective We tested the hypothesis that endolysosome stores of Fe 2+ were sufficient to control Aβ 42 -induced increases in mitochondrial Fe 2+ and ROS, mitochondrial depolarization, and cell death. Methods Using SH-SY5Y human neuroblastoma cells, we investigated the effects of Aβ 42 (500 nM) and Aβ 40 (500 nM) peptides on endolysosome and mitochondrial stress responses. Results Aβ 42 but not Aβ 40 accumulated in and significantly decreased endolysosome Fe 2+ levels. Further, Aβ 42 significantly (1) de-acidified endolysosomes, (2) caused endolysosome damage, (3) caused impaired autophagy, (4) increased levels of cytosolic Fe 2+ and ROS, (5) increased levels of mitochondrial Fe 2+ 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 Fe 2+ appear to be important regulators of Aβ 42 -induced cytotoxicity and targeting these iron stores may lead to new therapeutics against AD-like pathology.