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Intracellular localization of amyloid beta peptide in SH-SY5Y neuroblastoma cells
Karolinska Inst, NVS, KI Alzheimers Dis Res Ctr, S-14186 Stockholm, Sweden.
KI-AlzheimerDisease Research Center, NVS, Novum, Karolinska Institutet, SE-141 57, Stockholm,Sweden.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences.
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2013 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 37, no 4, 713-733 p.Article in journal (Refereed) Published
Abstract [en]

Amyloid-beta peptide (A beta), the main component of Alzheimer's disease (AD) senile plaques, has been found to accumulate within the lysosomal compartment of AD neurons. We have previously shown that in differentiated SH-SY5Y neuroblastoma cells cultured under normal conditions, the majority of A beta is localized extralysosomally, while oxidative stress significantly increases intralysosomal A beta content through activation of macroautophagy. It is, however, not clear which cellular compartments contain extralysosomal A beta in intact SH-SY5Y cells, and how oxidative stress influences the distribution of extralysosomal A beta. Using confocal laser scanning microscopy and immunoelectron microscopy, we showed that in differentiated neuroblastoma cells cultured under normal conditions A beta (A beta(40), A beta(42), and A beta oligomers) is colocalized with both membrane-bound organelles (endoplasmic reticulum, Golgi complexes, multivesicular bodies/late endosomes, lysosomes, exocytotic vesicles and mitochondria) and non-membrane-bound cytosolic structures. Neuroblastoma cells stably transfected with A beta PP Swedish KM670/671NL double mutation showed enlarged amount of A beta colocalized with membrane compartments. Suppression of exocytosis by 5 nM tetanus toxin resulted in a significant increase of the amount of cytosolic A beta as well as A beta colocalized with exocytotic vesicles, endoplasmic reticulum, Golgi complexes, and lysosomes. Hyperoxia increased A beta localization in the endoplasmic reticulum, Golgi apparatus, mitochondria, and lysosomes, but not in the secretory vesicles. These results indicate that in SH-SY5Y neuroblastoma cells intracellular A beta is not preferentially localized to any particular organelle and, to a large extent, is secreted from the cells. Challenging cells to hyperoxia, exocytosis inhibition, or A beta overproduction increased intracellular A beta levels but did not dramatically changed its localization pattern.

Place, publisher, year, edition, pages
IOS Press, 2013. Vol. 37, no 4, 713-733 p.
Keyword [en]
Alzheimer’s disease, Amyloid β-protein, Endosomes, Exocytosis, Lysosomes
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-73411DOI: 10.3233/JAD-122455ISI: 000325649500007OAI: oai:DiVA.org:liu-73411DiVA: diva2:472000
Available from: 2012-01-03 Created: 2012-01-03 Last updated: 2017-12-08Bibliographically 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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Hallbeck, MartinJerhammar, FredrikMarcusson, Jan

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Hallbeck, MartinJerhammar, FredrikMarcusson, Jan
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Experimental PathologyFaculty of Health SciencesDepartment of Clinical Pathology and Clinical GeneticsOto-Rhiono-Laryngology and Head & Neck SurgeryGeriatricDepartment of Geriatric Medicine in Linköping
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Journal of Alzheimer's Disease
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