title: A free radical-generating system regulates AβPP metabolism/processing: involvement of the ubiquitin/proteasome and autophagy/lysosome pathways.
abstract: Oxidative stress is an early event in the pathogenesis of Alzheimer's disease (AD). We previously reported that, in SK-N-MC cells, the xanthine/xanthine oxidase (X-XOD) free radical generating system regulates the metabolism/processing of the amyloid-β protein precursor (AβPP). Oxidative stress alters the two main cellular proteolytic machineries, the ubiquitin/proteasome (UPS) and the autophagy/lysosome systems, and recent studies have established connections between the malfunctioning of these and the pathogenesis of AD. The aim of the present work was to examine the involvement of these proteolytic systems in the regulation of AβPP metabolism by X-XOD. The proteasome inhibitor MG132 was found to accelerate the metabolism/processing of AβPP promoted by X-XOD because it significantly enhances the secretion of α-secretase-cleaved soluble AβPP and also the levels of both carboxy-terminal fragments (CTFs) produced by α- and β-secretase. Further, MG132 modulated the intracellular accumulation of holo-AβPP and/or AβPP CTFs. This indicates that the X-XOD modulation of AβPP metabolism/processing involves the UPS pathway. With respect to the autophagy/lysosome pathway, the AβPP processing and intracellular location patterns induced by X-XOD treatment closely resembled those produced by the lysosome inhibitor ammonium chloride. The present results suggest that the regulation of AβPP metabolism/processing by mild oxidative stress requires UPS activity with a simultaneous reduction in that of the autophagy/lysosome system.
authors.affiliation: Centro de Investigación en Red de Enfermedades Neurodegenerativas (CIBERNED), Spain. mrecuero@cbm.uam.es
authors.forename: María
authors.initials: M
authors.lastname: Recuero
authors.forename: Victor A
authors.initials: VA
authors.lastname: Munive
authors.forename: Isabel
authors.initials: I
authors.lastname: Sastre
authors.forename: Jesús
authors.initials: J
authors.lastname: Aldudo
authors.forename: Fernando
authors.initials: F
authors.lastname: Valdivieso
authors.forename: María J
authors.initials: MJ
authors.lastname: Bullido
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D001343:Autophagy / Q000502:physiology*; D045744:Cell Line, Tumor; D005609:Free Radicals / Q000494:pharmacology*; D006801:Humans; D008247:Lysosomes / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D025801:Ubiquitin / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D016564:Amyloid beta-Protein Precursor; D005609:Free Radicals; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex