uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • 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
Amyloid-β Protofibrils in Alzheimer´s Disease: Focus on Antibodies, Inflammation and Astrocytes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Soluble amyloid-beta (Aβ) aggregates, including Aβ protofibrils, play a central role in Alzheimer’s disease (AD) and constitute a potential diagnostic biomarker and a therapeutic target. Aβ protofibrils promote synapse dysfunction and neurodegeneration, but the mechanisms behind these effects remain unclear. The aim of this thesis was to increase the knowledge of Aβ protofibrils in AD pathology.

When measuring low abundant antigens, such as soluble Aβ aggregates, in plasma and CSF by immunoassays, there is a possibility of interference by heterophilic antibodies (HA). In paper I, we show that HA generate false positive signals, by cross-binding the assay antibodies, when plasma and CSF from AD patients and healthy controls were analyzed for soluble Aβ aggregates, using sandwich ELISAs.

Natural anti-Aβ antibodies exist in AD patients and healthy individuals. Circulating Aβ and anti-Aβ antibodies may form immune complexes, masking epitopes on the anti-Aβ antibody, which makes the anti-Aβ antibody concentration difficult to measure. In paper II, the ELISpot technique enabled us to successfully measure B cell production of anti-Aβ antibodies. Our results show that anti-Aβ protofibril antibody production is present in both AD patients and healthy individuals, but is significantly higher in AD patients, indicating that the immune system attempt to eliminate the toxic Aβ species.

Insufficient lysosomal degradation is proposed to cause sporadic AD. In paper III, we used a co-culture system of astrocytes, neurons and oligodendrocytes, to clarify the role of astrocytes in Aβ protofibril clearance. Astrocytes are the most prominent glial cell type in the brain, but their role in AD remains elusive. We found that astrocytes effectively engulf, but inefficiently degrade Aβprotofibrils. This result in a high intracellular load of toxic, partly N-terminally truncated Aβ and lysosomal dysfunction. Moreover, we found that secretion of microvesicles, containing N-terminally truncated Aβ, induce neuronal apoptosis. In paper IV, we show that treatment with the protofibril selective antibody mAb158 lead to enhanced Aβ clearance and thereby prevent Aβ neurotoxicity.

Taken together, this thesis contributes with important knowledge on the role of Aβ protofibrils in AD pathogenesis and technical aspects that should be considered when measuring Aβ in human tissues.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. , 72 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1147
Keyword [en]
Alzheimer's Disease, Amyloid-beta, Protofibrils, ELISA, ELISpot, Astrocyte, Monoclonal Antibody, Immunofluorescence
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-264647ISBN: 978-91-554-9373-8 (print)OAI: oai:DiVA.org:uu-264647DiVA: diva2:861224
Public defence
2015-12-04, Rudbecksalen, Rudbeckslaboratoriet, Dag Hammarskjöldsväg 20, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2015-11-13 Created: 2015-10-15 Last updated: 2016-01-14Bibliographically approved
List of papers
1. Interference from Heterophilic Antibodies in Amyloid-beta Oligomer ELISAs
Open this publication in new window or tab >>Interference from Heterophilic Antibodies in Amyloid-beta Oligomer ELISAs
Show others...
2010 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 21, no 4, 1295-1301 p.Article in journal (Refereed) Published
Abstract [en]

Amyloid-beta (Abeta) oligomers of different sizes and forms have recently been the focus for many Alzheimer's disease (AD) researchers. Various immunoassays have been used to detect low concentrations of these elusive Abeta species in different forms of human samples using little or no sample dilutions. However, the possibility that positive results may be caused by interference from heterophilic antibodies (HA) is often overlooked. HA, which recognize immunoglobulins from other species, are present in human plasma and cerebrospinal fluid (CSF) and may cause interference in sandwich immunoassays like enzyme-linked immunosorbent assays (ELISAs) by cross-binding the capture and detection antibodies of the assay. They thus may generate a false positive signal. Here we show that when assessing the Abeta oligomer content in plasma samples from 44 individuals with a sandwich ELISA, none of the 21 positive signals remained when the assay was repeated in the presence of factors blocking HA. Similarly, in CSF samples from 104 individuals, the signals from the 22 positive samples were strongly reduced when analyzed after anti-HA treatment. Taken together, HA interference is a problem that needs to be addressed when measuring low levels of an antigen in human plasma and CSF samples.

Place, publisher, year, edition, pages
IOS Press, 2010
Keyword
Alzheimer's disease, Heterophilic antibodies, ELISA
National Category
Neurology
Research subject
Geriatrics
Identifiers
urn:nbn:se:uu:diva-132732 (URN)10.3233/JAD-2010-100609 (DOI)000283049700021 ()20693634 (PubMedID)
Note

Title also written as: Interference from Heterophilic Antibodies in Amyloid-β Oligomer ELISAs

Available from: 2010-10-26 Created: 2010-10-26 Last updated: 2017-12-12Bibliographically approved
2. Increased Number of Plasma B Cells Producing Autoantibodies Against A beta(42) Protofibrils in Alzheimer's Disease
Open this publication in new window or tab >>Increased Number of Plasma B Cells Producing Autoantibodies Against A beta(42) Protofibrils in Alzheimer's Disease
Show others...
2015 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 48, no 1, 63-72 p.Article in journal (Refereed) Published
Abstract [en]

The Alzheimer's disease (AD)-related peptide amyloid-beta (A beta) has a propensity to aggregate into various assemblies including toxic soluble A beta protofibrils. Several studies have reported the existence of anti-A beta antibodies in humans. However, it is still debated whether levels of anti-A beta antibodies are altered in AD patients compared to healthy individuals. Formation of immune complexes with plasma A beta makes it difficult to reliably measure the concentration of circulating anti-A beta antibodies with certain immunoassays, potentially leading to an underestimation. Here we have investigated anti-A beta antibody production on a cellular level by measuring the amount of anti-A beta antibody producing cells instead of the plasma level of anti-A beta antibodies. To our knowledge, this is the first time the anti-A beta antibody response in plasma has been compared in AD patients and age-matched healthy individuals using the enzyme-linked immunospot (ELISpot) technique. Both AD patients and healthy individuals had low levels of B cells producing antibodies binding A beta(40) monomers, whereas the number of cells producing antibodies toward A beta(42) protofibrils was higher overall and significantly higher in AD compared to healthy controls. This study shows, by an alternative and reliable method, that there is a specific immune response to the toxic A beta protofibrils, which is significantly increased in AD patients.

Keyword
Amyloid-beta, amyloid-beta protofibrils, anti-amyloid-beta antibodies, enzyme-linked immunospot assay
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-264340 (URN)10.3233/JAD-150236 (DOI)000360931700007 ()26401929 (PubMedID)
Funder
Swedish Research Council, 2012-2172
Available from: 2015-10-09 Created: 2015-10-09 Last updated: 2017-12-01Bibliographically approved
3. Accumulation of amyloid-β by astrocytes result in enlarged endosomes and microvesicle-induced apoptosis of neurons
Open this publication in new window or tab >>Accumulation of amyloid-β by astrocytes result in enlarged endosomes and microvesicle-induced apoptosis of neurons
Show others...
2016 (English)In: Molecular Neurodegeneration, ISSN 1750-1326, E-ISSN 1750-1326Article in journal (Refereed) Published
Keyword
Alzheimer's Disease, protofibril, glia, phagocytosis, degradation, enlarged vacuole, microvesicle
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-264222 (URN)
Available from: 2015-10-15 Created: 2015-10-07 Last updated: 2017-12-01
4. The Aβ protofibril selective antibody mAb158 prevents accumulation of Aβ in astrocytes and rescues neurons from Aβ-induced cell death.
Open this publication in new window or tab >>The Aβ protofibril selective antibody mAb158 prevents accumulation of Aβ in astrocytes and rescues neurons from Aβ-induced cell death.
Show others...
(English)In: Article in journal (Refereed) Submitted
Keyword
Alzheimer’s disease, amyloid-β, antibody, clearance, astrocyte, neuron
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-264223 (URN)
Available from: 2015-10-15 Created: 2015-10-07 Last updated: 2017-11-28

Open Access in DiVA

fulltext(1541 kB)249 downloads
File information
File name FULLTEXT01.pdfFile size 1541 kBChecksum SHA-512
08a0acc0d2f952a0772e0c08e9d0a84cebcb780e72c58f60ee955965bff29f8f24e9b9b8c7f2d791efeb2728035c48fa1f1f2d82d91d6f6c355bbf91f377d59a
Type fulltextMimetype application/pdf
Buy this publication >>

Authority records BETA

Söllvander, Sofia

Search in DiVA

By author/editor
Söllvander, Sofia
By organisation
Department of Public Health and Caring Sciences
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 249 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

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 1983 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • 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