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- W4377029364 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<sub>1-42</sub>) 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 (Fe<sup>2+</sup>) induced ROS generation via Fenton-like chemical reactions. Because endolysosome de-acidification can induce lysosome stress responses that cause Fe<sup>2+</sup> to be released from endolysosomes it was important for us to determine the extent to which and mechanisms by which Aβ<sub>1-42</sub> 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 (Fe<sup>3+</sup>) it prevented the efflux of the readily releasable endolysosome stores of Fe<sup>2+</sup> into the cytosol and other organelles. Thus, it was important for us to determine the effects of Aβ<sub>1-42</sub> 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<sub>1-42</sub> de-acidified endolysosomes, decreased endolysosome Fe<sup>2+</sup> levels, increased cytosolic Fe<sup>2+</sup> and ROS levels, increased mitochondria Fe<sup>2+</sup> and ROS levels, depolarized mitochondrial membrane potentials, and increased cell death; effects all blocked by DFO. Therefore, an increased understanding of Aβ<sub>1-42 </sub>-induced endolysosome iron disruption may provide novel insight into the Aβ<sub>1-42 </sub>burden of AD and possibly new therapeutic targets. <b>Support/Funding Information:</b> [P20GM139759, P30GM100329, U54GM115458, R01MH100972, R01MH105329, R01MH119000, 2R01NS065957, 2R01DA032444]" @default.
- W4377029364 created "2023-05-19" @default.
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- W4377029364 date "2023-05-18" @default.
- W4377029364 modified "2023-09-29" @default.
- W4377029364 title "Amyloid Beta Protein (Aβ<sub>1-42</sub>) induced Endolysosome Iron Dyshomeostasis caused increases in Reactive Oxygen Species, Mitochondrial Depolarization, and Neurotoxicity" @default.
- W4377029364 doi "https://doi.org/10.1124/jpet.122.212100" @default.
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