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Increase in beta-Amyloid Levels in Cerebrospinal Fluid of Children with Down Syndrome
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences. (Geriatrics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Barnendokrinologisk forskning/Tuvemo)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Barnendokrinologisk forskning/Gustafsson)
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2007 (English)In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 24, no 5, 369-374 p.Article in journal (Refereed) Published
Abstract [en]

Background: Individuals with Down syndrome (DS) invariably develop Alzheimer's disease (AD) during their life span. It is therefore of importance to study young DS patients when trying to elucidate early events in AD pathogenesis. Aim: To investigate how levels of different amyloid- (A) peptides, as well as tau and phosphorylated tau, in cerebrospinal fluid (CSF) from children with DS change over time. The first CSF sample was taken at 8 months and the following two samples at 20-40 and 54 months of age. Results: Individual levels of the A peptides, as well as total A levels in CSF increased over time when measured with Western blot. Tau in CSF decreased whereas there was no change in levels of phosphorylated tau over time. Conclusion: The increasing levels of A in CSF during early childhood of DS patients observed in this study are probably due to the trisomy of the A precursor APP, which leads to an overproduction of A. Despite the increased CSF concentrations of A, there were no signs of an AD-indicating tau pattern in CSF, since the levels of total tau decreased and phosphorylated tau remained unchanged. This observation further strengthens the theory of A pathology preceding tau pathology in AD.

Place, publisher, year, edition, pages
2007. Vol. 24, no 5, 369-374 p.
Keyword [en]
Alzheimer's disease, Down syndrome, Amyloid-beta, Tau, Cerebrospinal fluid
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-11726DOI: 10.1159/000109215ISI: 000250314400007PubMedID: 17914261OAI: oai:DiVA.org:uu-11726DiVA: diva2:39495
Available from: 2008-04-14 Created: 2008-04-14 Last updated: 2017-12-11Bibliographically 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, HilleviAnnerén, GöranGustafsson, JanWester, UlrikaLannfelt, Lars

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Dementia and Geriatric Cognitive Disorders
Medical and Health Sciences

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