期刊
NEUROSCIENCE LETTERS
卷 394, 期 3, 页码 184-189出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.neulet.2005.10.035
关键词
Alzheimer disease; amyloid beta-protein; autophagy; lysosomes; reactive oxygen species
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 (A beta). A beta cytotoxicity has been found dependent on lysosomes, which are abundant in AD neurons and are shown to partially co-localize with A beta. To determine whether oxidative stress has any influence on the relationship between lysosomes and A beta(1-42) (the most toxic form of A beta), we studied the effect of hyperoxia (40% versus 8% ambient oxygen) on the intracellular localization of A beta(1-42) (assessed by immunocytochemistry) in retinoic acid differentiated SH-SY5Y neuroblastoma cells maintained in serum-free OptiMEM medium. In control cells, A beta(1-42) was mainly localized to small non-lysosomal cytoplasmic granules. Only occasionally A beta(1-42) was found in large (over I mu m) lysosomal-associated. membrane protein 2 positive vacuoles, devoid of the early endosomal marker rab5. These large A beta(1-42) -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 A beta(1-42)-positive lysosomes due to hyperoxia. In parallel experiments, intralysosomal accumulation of A beta(1-40) following oxidative stress has been found as well. The results suggest that A beta can be autophagocytosed and its accumulation within neuronal lysosomes is enhanced by oxidative stress. (c) 2005 Elsevier Ireland Ltd. All rights reserved.
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