liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Spreading of Amyloid-β Peptides via Neuritic Cell-to-cell Transfer Is Dependent on Insufficient Cellular Clearance
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
Show others and affiliations
2014 (English)In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 65, p. 82-92Article in journal (Refereed) Published
Abstract [en]

The spreading of pathology through neuronal pathways is likely to be the cause of the progressive cognitive loss observed in Alzheimer's disease (AD) and other neurodegenerative diseases. We have recently shown the propagation of AD pathology via cell-to-cell transfer of oligomeric amyloid beta (Aβ) residues 1-42 (oAβ1-42) using our donor-acceptor 3-D co-culture model. We now show that different Aβ-isoforms (fluorescently labeled 1-42, 3(pE)-40, 1-40 and 11-42 oligomers) can transfer from one cell to another. Thus, transfer is not restricted to a specific Aβ-isoform. Although different Aβ isoforms can transfer, differences in the capacity to clear and/or degrade these aggregated isoforms result in vast differences in the net amounts ending up in the receiving cells and the net remaining Aβ can cause seeding and pathology in the receiving cells. This insufficient clearance and/or degradation by cells creates sizable intracellular accumulations of the aggregation-prone Aβ1-42 isoform, which further promotes cell-to-cell transfer; thus, oAβ1-42 is a potentially toxic isoform. Furthermore, cell-to-cell transfer is shown to be an early event that is seemingly independent of later appearances of cellular toxicity. This phenomenon could explain how seeds for the AD pathology could pass on to new brain areas and gradually induce AD pathology, even before the first cell starts to deteriorate, and how cell-to-cell transfer can act together with the factors that influence cellular clearance and/or degradation in the development of AD.

Place, publisher, year, edition, pages
Elsevier, 2014. Vol. 65, p. 82-92
Keywords [en]
Alzheimer's disease, Amyloid-β oligomers, Cell-to-cell transfer, Intracellular accumulation, Prion-like propagation
National Category
Cell Biology
Identifiers
URN: urn:nbn:se:liu:diva-103179DOI: 10.1016/j.nbd.2013.12.019ISI: 000333546300008PubMedID: 24412310OAI: oai:DiVA.org:liu-103179DiVA, id: diva2:687455
Available from: 2014-01-14 Created: 2014-01-14 Last updated: 2019-10-14Bibliographically approved
In thesis
1. Neuron-to-neuron propagation of neurodegenerative proteins; relation to degradative systems
Open this publication in new window or tab >>Neuron-to-neuron propagation of neurodegenerative proteins; relation to degradative systems
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are defined by neurodegeneration and accumulations of misfolded proteins that spread through the brain in a well characterized manner. In AD these accumulations consist mainly of β-amyloid (Aβ) and tau, while in PD, α-synuclein (α-syn) make up the characteristic lewy pathology. 

   The general aim of this thesis was to investigate mechanisms associated with neurotoxic peptide activity by Aβ, tau and α-syn in relation to cellular degradation and transfer with a cell-to-cell transfer model system.

   We found that intercellular transfer of oligomeric Aβ occurs independently of isoform. However, the amount of transfer correlates with each isoforms ability to resist degradation or cellular clearance. The Aβ1-42 isoform showed particular resistance to clearance, which resulted in higher levels of cell-to-cell transfer of the isoform and lysosomal stress caused by accumulation.

   As Aβ accumulations can inhibit the proteasomal degradation we investigated how reduced proteasomal degradation affected neuron-like cells. We found increased levels of phosphorylated tau protein, disturbed microtubule stability and impaired neuritic transport after reduced proteasomal activity. These changes was partly linked to c-Jun and ERK 1/2 kinase activity.

   We could also show that α-syn transferred from cell-to-cell in our model system, with a higher degree of transfer for the larger oligomer and fibrillar species. Similar to Aβ, α-syn mainly colocalized with lysosomes, before and after transfer.

    Lastly, we have developed our cell-to-cell transfer system into a model suitable for high throughput screening (HTS). The type of cells have been upgraded from SH-SY5Y cells to induced pluripotent stem cells (iPSCs), with a differentiation profile more similar to mature neurons. The next step will be screening a small molecular library for substances with inhibitory effect on cell-to-cell transfer of Aβ peptides. 

   The importance of the degradative systems in maintaining protein homeostasis and prevent toxic accumulations in general is well known. Our findings shows the importance of these systems for neurodegenerative diseases and also highlight the link between degradation and cell-to-cell transfer. To restore or enhance the degradative systems would be an interesting avenue to treat neurodegenerative diseases. Another way would be to inhibit the transfer of misfolded protein aggregates. By using the HTS model we developed, a candidate substance with good inhibitory effect on transfer can hopefully be found.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2017. p. 63
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1535
Keywords
Cell-to-cell transfer, beta-amyloid, Alzheimer's disease, degradation, proteasome, alpha-synuclein, Parkinson's disease, high throughput screening model
National Category
Cell and Molecular Biology Neurosciences
Identifiers
urn:nbn:se:liu:diva-134667 (URN)10.3384/diss.diva-134667 (DOI)9789176857014 (ISBN)
Public defence
2017-03-23, Linden, Campus US, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2017-02-27 Created: 2017-02-23 Last updated: 2019-10-28Bibliographically approved

Open Access in DiVA

fulltext(1657 kB)879 downloads
File information
File name FULLTEXT01.pdfFile size 1657 kBChecksum SHA-512
7e8560b08e9764377f981b4737125708585cbda11154b4729bc9fb1e80389a9f0bff2c6d5dee71fd82d46e16e6b54f682927a266ce60b11063774518c56a5626
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Authority records

Domert, JakobAgholme, LottaBrorsson, Ann-ChristinMarcusson, JanHallbeck, MartinNath, Sangeeta

Search in DiVA

By author/editor
Domert, JakobAgholme, LottaBrorsson, Ann-ChristinMarcusson, JanHallbeck, MartinNath, Sangeeta
By organisation
Division of Cell BiologyFaculty of Health SciencesChemistryThe Institute of TechnologyDivision of NeuroscienceDivision of Inflammation MedicineDepartment of Clinical Pathology and Clinical Genetics
In the same journal
Neurobiology of Disease
Cell Biology

Search outside of DiVA

GoogleGoogle Scholar
Total: 884 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 1483 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf