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Autophagy of amyloid beta-protein in differentiated neuroblastoma cells exposed to oxidative stress
Linköping University, Department of Neuroscience and Locomotion, Geriatrics. Linköping University, Faculty of Health Sciences.
Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Oto-Rhiono-Laryngology and Head & Neck Surgery. Östergötlands Läns Landsting, Reconstruction Centre, Department of ENT - Head and Neck Surgery UHL.
Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Geriatrics. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
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2006 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 394, no 3, 184-189 p.Article in journal (Refereed) Published
Abstract [en]

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 (Aβ). Aβ cytotoxicity has been found dependent on lysosomes, which are abundant in AD neurons and are shown to partially co-localize with Aβ. To determine whether oxidative stress has any influence on the relationship between lysosomes and Aβ1-42 (the most toxic form of Aβ), we studied the effect of hyperoxia (40% versus 8% ambient oxygen) on the intracellular localization of Aβ1-42 (assessed by immunocytochemistry) in retinoic acid differentiated SH-SY5Y neuroblastoma cells maintained in serum-free OptiMEM medium. In control cells, Aβ1-42 was mainly localized to small non-lysosomal cytoplasmic granules. Only occasionally Aβ1-42 was found in large (over 1 μm) lysosomal-associated membrane protein 2 positive vacuoles, devoid of the early endosomal marker rab5. These large Aβ1-42-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 Aβ1-42-positive lysosomes due to hyperoxia. In parallel experiments, intralysosomal accumulation of Aβ1-40 following oxidative stress has been found as well. The results suggest that Aβ can be autophagocytosed and its accumulation within neuronal lysosomes is enhanced by oxidative stress. © 2005 Elsevier Ireland Ltd. All rights reserved.

Place, publisher, year, edition, pages
2006. Vol. 394, no 3, 184-189 p.
Keyword [en]
Alzheimer disease; Amyloid beta-protein; Autophagy; Lysosomes; Reactive oxygen species
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-35894DOI: 10.1016/j.neulet.2005.10.035Local ID: 28972OAI: oai:DiVA.org:liu-35894DiVA: diva2:256742
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Lysosomal Involvement in the Pathogenesis of Alzheimer's Disease
Open this publication in new window or tab >>Lysosomal Involvement in the Pathogenesis of Alzheimer's Disease
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alzheimer’s disease (AD), the major cause of senile dementia, is associated with progressive formation of neurofibrillary tangles and extraneuronal plaques composed of amyloid beta peptide (Aβ). Aβ has been also found within Alzheimer neurons in association with the lysosomal system, an acidic vacuolar compartment possessing numerous hydrolytic enzymes. Lysosomes have been shown to be involved in both the formation of Aβ and its toxicity to neurons. Another line of evidence implicates oxidative stress as an important factor in the development of AD. It is reported that oxidative damage is one of the earliest changes in AD and plays an important role in the development of the disease. Although both the lysosomal system and reactive oxygen species are involved in AD, the mechanisms of this involvement are not well understood.

To gain insight into the relationship between oxidative stress and the lysosomal system in AD pathogenesis, we focused our study on: 1) The effect of oxidative stress on intracellular distribution of Aβ; 2) the role of endogenous Aβ in oxidant-induced apoptosis; 3) the role of autophagy and APP processing in oxidant induced damage; and, 4) the intraneuronal localization of Aβ and its relationship to the lysosomal system.

In our study, hyperoxia (40% versus 8% ambient oxygen) was used as a model of mild oxidative stress in vitro, while transfected cells producing different amounts of Aβ were used to assess toxicity due to endogenous Aβ. It was found that: 1) oxidative stress induces autophagic uptake of Aβ, resulting in its partial accumulation within lysosomes; 2) oxidative stress can induce neuronal death through macroautophagy of Aβ and consequent lysosomal membrane permeabilization; 3) increased cellular Aβ production is associated with enhanced oxidative stress and enhanced macroautophagy, resulting in increased intralysosomal Aβ accumulation and consequent apoptosis; and, 4) in normal conditions, intracellular Aβ shows primarily cytosolic distribution, not related to lysosomes and other acidic vacuoles, endoplasmic reticulum, Golgi complexes, synaptic vesicles or mitochondria. Only a minor portion of Aβ shows partial colocalization with cellular organelles. Inhibition of secretion significantly increased Aβ colocalization with endoplasmic reticulum, Golgi complexes, synaptic vesicles and lysosomes, as well as the amount of mitochondrial and cytosolic Aβ.

Oxidative stress induces intralysosomal autophagy-generated Aβ accumulation, consequently causing lysosomal membrane permeabilization and apoptosis. Our findings provide a possible explanation of the interactive role of oxidative stress and lysosomal system in AD pathogenesis, and may be helpful for a future therapeutic strategy against AD.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. 55 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1282
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-73412 (URN)978-91-7393-005-5 (ISBN)
Public defence
2012-02-03, Berzeliussalen, ingång 65, Campus US, Linköpings universitet, Linköping, 13:00 (English)
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Available from: 2012-01-03 Created: 2012-01-03 Last updated: 2012-01-05Bibliographically approved

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Zheng, LinRoberg, KarinJerhammar, FredrikMarcusson, JanTerman, Alexei

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GeriatricsFaculty of Health SciencesOto-Rhiono-Laryngology and Head & Neck SurgeryDepartment of ENT - Head and Neck Surgery UHLPathologyDepartment of Geriatric Medicine
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