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

BackgroundAlzheimer'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.ObjectiveWe 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.MethodsUsing SH-SY5Y human neuroblastoma cells, we investigated the effects of Aβ42 (500 nM) and Aβ40 (500 nM) peptides on endolysosome and mitochondrial stress responses.ResultsAβ42 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.ConclusionsEndolysosome 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.