title: Autophagy of amyloid beta-protein in differentiated neuroblastoma cells exposed to oxidative stress.
abstract: Oxidative stress is considered important for the pathogenesis of Alzheimer disease (AD), which is characterized by the formation of senile plaques rich in amyloid beta-protein (Abeta). Abeta cytotoxicity has been found dependent on lysosomes, which are abundant in AD neurons and are shown to partially co-localize with Abeta. To determine whether oxidative stress has any influence on the relationship between lysosomes and Abeta1-42 (the most toxic form of Abeta), we studied the effect of hyperoxia (40% versus 8% ambient oxygen) on the intracellular localization of Abeta1-42 (assessed by immunocytochemistry) in retinoic acid differentiated SH-SY5Y neuroblastoma cells maintained in serum-free OptiMEM medium. In control cells, Abeta1-42 was mainly localized to small non-lysosomal cytoplasmic granules. Only occasionally Abeta1-42 was found in large (over 1 microm) lysosomal-associated membrane protein 2 positive vacuoles, devoid of the early endosomal marker rab5. These large Abeta1-42 -containing lysosomes were not detectable in the presence of serum (known to suppress autophagy), while their number increased dramatically (up to 24-fold) after exposure of cells to hyperoxia during 5 days. Activation of autophagy by hyperoxia was confirmed by transmission electron microscopy. Furthermore, an inhibitor of autophagic sequestration 3-methyladenine prevented the accumulation of Abeta1-42 -positive lysosomes due to hyperoxia. In parallel experiments, intralysosomal accumulation of Abeta1-40 following oxidative stress has been found as well. The results suggest that Abeta can be autophagocytosed and its accumulation within neuronal lysosomes is enhanced by oxidative stress.
authors.affiliation: Division of Geriatric Medicine, Faculty of Health Sciences, Linköping University, 58185 Linköping, Sweden. linzh@inr.liu.se
authors.forename: Lin
authors.initials: L
authors.lastname: Zheng
authors.forename: Karin
authors.initials: K
authors.lastname: Roberg
authors.forename: Fredrik
authors.initials: F
authors.lastname: Jerhammar
authors.forename: Jan
authors.initials: J
authors.lastname: Marcusson
authors.forename: Alexei
authors.initials: A
authors.lastname: Terman
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D003594:Cytoplasmic Granules / Q000378:metabolism; D006801:Humans; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D009447:Neuroblastoma / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D014212:Tretinoin / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D014212:Tretinoin