Oxidative stress induces macroautophagy of amyloid beta-protein and ensuing apoptosis
2009 (English)In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 46, no 3, 422-429 p.Article in journal (Refereed) Published
There is increasing evidence for the toxicity of intracellular amyloid beta-protein (A beta) to neurons and the involvement of lysosomes in this process in Alzheimer disease (AD). We have recently shown that oxidative stress, a recognized determinant of AD. enhances macroautophagy and leads to intralysosomal accumulation of A beta in Cultured neuroblastoma cells. We hypothesized that oxidative stress promotes AD by stimulating macroautophagy of A that further may induce cell death by destabilizing lysosomal membranes. To investigate such possibility, we compared the effects of hyperoxia (40% ambient oxygen) in cultured HEK293 cells that were transfected with an empty vector (Vector), wild-type APP (APPwt), or Swedish mutant APP (APPswe). Exposure to hyperoxia for 5 days increased the number of cells with A beta-containing lysosomes, as well as the number of apoptotic cells, compared to normoxic conditions. The rate of apoptosis in all three cell lines demonstrated dependence on intralysosomal A beta content (Vector<APPwt<APPswe). Furthermore, the degree of apoptosis was positively correlated with lysosomal membrane permeabilization, whereas inhibitors Of macroautophagy and lysosomal function decreased oxidant-induced apoptosis and diminished the differences in apoptotic response between different cell lines. These results suggest that oxidative stress can induce neuronal death through macroautophagy of A beta and consequent lysosomal membrane permeabilization, which may help explain the mechanisms behind neuronal loss in AD.
Place, publisher, year, edition, pages
2009. Vol. 46, no 3, 422-429 p.
Alzheimer disease, Amyloid beta-protein, Amyloid precursor protein, Apoptosis, Autophagy, Lysosomes, Oxidative stress, Free radicals
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-16625DOI: 10.1016/j.freeradbiomed.2008.10.043OAI: oai:DiVA.org:liu-16625DiVA: diva2:159538