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Oligomerization partially explains the lowering of Aβ42 in Alzheimer's disease cerebrospinal fluid
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. (Molecular Geriatrics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. (Molecular Geriatrics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. (Molecular Geriatrics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. (Molecular Geriatrics)
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2009 (English)In: Neuro-degenerative diseases, ISSN 1660-2862, Vol. 6, no 4, 139-147 p.Article in journal (Refereed) Published
Abstract [en]

Background/aim: The lowering of natively analyzed Aβ42 in cerebrospinal fluid (CSF) is used as a diagnostic tool in Alzheimer’s disease (AD). Presence of Aβ oligomers can interfere with such analyses causing underestimation of Aβ levels due to epitope masking. The aim was to investigate if the lowering of CSF Aβ42 seen is caused by oligomerization. Methods: Aβ42 was analyzed under both denaturing and non-denaturing conditions. An Aβ42 oligomer ratio was calculated from these quantifications. Presence of oligomers leads to Aβ42 epitope masking during non-denaturing assays, resulting in a higher ratio. Results: The Aβ42 oligomer ratio was used for assessment of oligomerized Aβ in human CSF, after being evaluated in transgenic mouse brain homogenates. AD and mild cognitive impairment (MCI) samples displayed the expected decrease in natively measured Aβ42 compared to healthy controls and frontotemporal dementia, but not when analyzing under denaturing conditions. Accordingly, AD and MCI CSF had a higher Aβ42 oligomer ratio in CSF. Conclusion: Combining denaturing and non-denaturing quantifications of Aβ42 into an oligomer ratio enables assessment of Aβ oligomers in biological samples. The increased Aβ42 oligomer ratio for AD and MCI indicates presence of oligomers in CSF and that the lowering of natively measured Aβ42 is caused by oligomerization.

Place, publisher, year, edition, pages
2009. Vol. 6, no 4, 139-147 p.
Keyword [en]
Alzheimer’s disease, CSF, Amyloid-β, oligomers
National Category
Medical and Health Sciences
Research subject
Geriatrics
Identifiers
URN: urn:nbn:se:uu:diva-98510DOI: 10.1159/000225376ISI: 000269623400001PubMedID: 19521063OAI: oai:DiVA.org:uu-98510DiVA: diva2:174743
Available from: 2009-02-24 Created: 2009-02-24 Last updated: 2010-07-08Bibliographically approved
In thesis
1. Soluble amyloid-β aggregates in Alzheimer’s disease
Open this publication in new window or tab >>Soluble amyloid-β aggregates in Alzheimer’s disease
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Soluble oligomeric aggregates of the amyloid-β (Aβ) peptide are suggested to initiate Alzheimer's disease (AD), leading to impaired synapse signalling, widespread neuronal death and loss of cognitive functions. These aggregates seem tightly linked to disease progression, and have therefore gained much attention as potential novel disease markers. In this thesis soluble oligomeric Aβ aggregates in general, and the Aβ protofibril species in particular, have been investigated with the aim to quantify and determine their role in AD pathogenesis.

Sandwich-ELISAs specifically measuring Aβ42 peptides are widely used both in AD research and as complements for clinical diagnosis. Here it was demonstrated that presence of soluble Aβ aggregates disturbs such analyses, making it difficult to interpret the results. This discovery was made through analyses of samples from cell- and mouse models carrying the AD causing 'Arctic' APP mutation. When analyzed by ELISA, Aβ42 levels were reduced in Arctic samples, in contrast to levels measured by denaturing SDS-PAGE Western blot. The same divergence in Aβ42-levels between analyses was observed in CSF samples from Down syndrome infants. The discrepancy between methods was hypothesized to be due to presence of soluble Aβ aggregates leading to impaired ELISA detection caused by epitope masking. This was confirmed by developing a protofibril specific ELISA, by which samples from Arctic cell- and mouse models were demonstrated to have enhanced Aβ protofibril levels.

AD patients have reduced ELISA-measured Aβ42-levels in CSF compared to healthy controls. To test if this reduction was due to oligomeric Aβ species present in AD CSF, Aβ42-levels were analyzed under both denaturing and non-denaturing conditions. These two measures were combined and an Aβ42 oligomer ratio established. Higher ratios were found in AD patients than healthy controls, implying that Aβ oligomers are present in CSF during Alzheimer pathogenesis. The observations from AD patients and young Down syndrome individuals suggest that Aβ42 oligomer formation is an early mechanism of AD pathogenesis, which potentially could be used as a biomarker to monitor disease development.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 69 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 430
National Category
Geriatrics
Research subject
Geriatrics
Identifiers
urn:nbn:se:uu:diva-98512 (URN)978-91-554-7441-6 (ISBN)
Public defence
2009-04-17, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2009-03-25 Created: 2009-02-24 Last updated: 2009-03-27Bibliographically approved

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Englund, Hillevi

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