Amyloid Beta Protein (Aβ1-42) induced Endolysosome Iron Dyshomeostasis caused increases in Reactive Oxygen Species, Mitochondrial Depolarization, and Neurotoxicity

Abstract

<b>Abstract ID 21210</b> <b>Poster Board 130</b> Alzheimer’s disease (AD) is a widely prevalent age-associated neurodegenerative disease that is characterized clinically by decreased cognitive abilities and dementia as well as pathologically by the presence of amyloid beta plaques and intraneuronal accumulations of the highly fibrillogenic amyloid beta 1-42 (Aβ_1-42) protein and hyperphosphorylated tau protein. Implicated as well in the pathogenesis of AD are increased levels of reactive oxygen species (ROS) and iron dyshomeostasis. Amyloidogenesis is well known to occur in endolysosomes; acidic organelles that amongst other things contain high levels of divalent cations and these cations are released from endolysosomes when de-acidified. Endolysosomes are considered “master regulators of iron homeostasis”, and neuronal cell death and neurodegenerative disorders continue to be linked to ferrous iron (Fe²⁺) induced ROS generation via Fenton-like chemical reactions. Because endolysosome de-acidification can induce lysosome stress responses that cause Fe²⁺ to be released from endolysosomes it was important for us to determine the extent to which and mechanisms by which Aβ_1-42 affect endolysosomes and induce neuronal cell death. Recently, the endolysosome-specific iron chelator deferoxamine (DFO) was found to reduce the amyloid beta burden in AD but by unclear mechanisms. We reported previously that DFO is endocytosed and by chelating endolysosome stores of ferric iron (Fe³⁺) it prevented the efflux of the readily releasable endolysosome stores of Fe²⁺ into the cytosol and other organelles. Thus, it was important for us to determine the effects of Aβ_1-42 on the endolysosome iron pool that might lead to an iron imbalance and increased ROS. Here, using SH-SY5Y neuroblastoma cells we show that Aβ_1-42 de-acidified endolysosomes, decreased endolysosome Fe²⁺ levels, increased cytosolic Fe²⁺ and ROS levels, increased mitochondria Fe²⁺ and ROS levels, depolarized mitochondrial membrane potentials, and increased cell death; effects all blocked by DFO. Therefore, an increased understanding of Aβ_1-42-induced endolysosome iron disruption may provide novel insight into the Aβ_1-42burden of AD and possibly new therapeutic targets. <b>Support/Funding Information:</b> [P20GM139759, P30GM100329, U54GM115458, R01MH100972, R01MH105329, R01MH119000, 2R01NS065957, 2R01DA032444]