Soluble amyloid-β aggregates in Alzheimer’s disease

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Englund, Hillevi,1980-Uppsala universitet,Institutionen för folkhälso- och vårdvetenskap,Molecular Geriatrics (author)

Soluble amyloid-β aggregates in Alzheimer’s disease

BookEnglish2009

Publisher, publication year, extent ...

Uppsala :Acta Universitatis Upsaliensis,2009
69 s.
electronicrdacarrier

Numbers

LIBRIS-ID:oai:DiVA.org:uu-98512
ISBN:9789155474416
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-98512URI

Supplementary language notes

Language:English
Summary in:English

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SwePubSwePub

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Subject category:vet swepub-contenttype
Subject category:dok swepub-publicationtype

Series

Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine,1651-6206 ;430

Notes

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.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Geriatrik hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Geriatrics hsv//eng
Geriatrics and medical gerontology
Geriatrik och medicinsk gerontologi
Geriatrics
geriatrik

Added entries (persons, corporate bodies, meetings, titles ...)

Ekholm Pettersson, Frida,PhDUppsala universitet,Geriatrik (thesis advisor)
Nilsson, Lars NG,DocentUppsala universitet,Geriatrik (thesis advisor)
Lannfelt, Lars,ProfessorUppsala universitet,Geriatrik (thesis advisor)
Walsh, Dominic M,ProfessorDepartment for Psychiatry, University of Goettingen (opponent)
Uppsala universitetInstitutionen för folkhälso- och vårdvetenskap (creator_code:org_t)

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