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Soluble amyloid-β aggregates in Alzheimer’s disease
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap. (Molecular Geriatrics)
2009 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis , 2009. , s. 69
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 430
Nationell ämneskategori
Geriatrik
Forskningsämne
geriatrik
Identifikatorer
URN: urn:nbn:se:uu:diva-98512ISBN: 978-91-554-7441-6 (tryckt)OAI: oai:DiVA.org:uu-98512DiVA, id: diva2:174745
Disputation
2009-04-17, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2009-03-25 Skapad: 2009-02-24 Senast uppdaterad: 2009-03-27Bibliografiskt granskad
Delarbeten
1. Amyloid-β oligomers are inefficiently measured by enzyme-linked immunosorbent assay
Öppna denna publikation i ny flik eller fönster >>Amyloid-β oligomers are inefficiently measured by enzyme-linked immunosorbent assay
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2005 Ingår i: Annals of Neurology, ISSN 0364-5134, Vol. 58, nr 1, s. 147-150Artikel i tidskrift (Refereegranskat) Published
Identifikatorer
urn:nbn:se:uu:diva-95486 (URN)
Tillgänglig från: 2007-03-02 Skapad: 2007-03-02Bibliografiskt granskad
2. Increase in beta-Amyloid Levels in Cerebrospinal Fluid of Children with Down Syndrome
Öppna denna publikation i ny flik eller fönster >>Increase in beta-Amyloid Levels in Cerebrospinal Fluid of Children with Down Syndrome
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2007 (Engelska)Ingår i: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 24, nr 5, s. 369-374Artikel i tidskrift (Refereegranskat) 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.

Nyckelord
Alzheimer's disease, Down syndrome, Amyloid-beta, Tau, Cerebrospinal fluid
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-11726 (URN)10.1159/000109215 (DOI)000250314400007 ()17914261 (PubMedID)
Tillgänglig från: 2008-04-14 Skapad: 2008-04-14 Senast uppdaterad: 2017-12-11Bibliografiskt granskad
3. Sensitive ELISA detection of amyloid-β protofibrils in biological samples
Öppna denna publikation i ny flik eller fönster >>Sensitive ELISA detection of amyloid-β protofibrils in biological samples
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2007 (Engelska)Ingår i: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 103, nr 1, s. 334-345Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Amyloid-β (Aβ) protofibrils are known intermediates of the in vitro Aβ aggregation process and the protofibrillogenic Arctic mutation (APPE693G) provides clinical support for a pathogenic role of Aβ protofibrils in Alzheimer's disease (AD). To verify their in vivo relevance and to establish a quantitative Aβ protofibril immunoassay, Aβ conformation dependent monoclonal antibodies were generated. One of these antibodies, mAb158 (IgG2a), was used in a sandwich ELISA to specifically detect picomolar concentrations of Aβ protofibrils without interference from Aβ monomers or the amyloid precursor protein (APP). The specificity and biological significance of this ELISA was demonstrated using cell cultures and transgenic mouse models expressing human APP containing the Swedish mutation (APPKN670/671ML), or the Swedish and Arctic mutation in combination. The mAb158 sandwich ELISA analysis revealed presence of Aβ protofibrils in both cell and animal models, proving that Aβ protofibrils are formed not only in vitro, but also in vivo. Furthermore, elevated Aβ protofibril levels in the Arctic-Swedish samples emphasize the usefulness of the Arctic mutation as a model of enhanced protofibril formation. This assay provides a novel tool for investigating the role of Aβ protofibrils in AD and has the potential of becoming an important diagnostic assay.

Nyckelord
Alzheimer's disease, Amyloid-β protofibril, Conformation-dependent antibody, Protofibril-specific ELISA
Nationell ämneskategori
Medicin och hälsovetenskap
Forskningsämne
Geriatrik
Identifikatorer
urn:nbn:se:uu:diva-98511 (URN)10.1111/j.1471-4159.2007.04759.x (DOI)000249949700030 ()17623042 (PubMedID)
Tillgänglig från: 2009-02-24 Skapad: 2009-02-24 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
4. Oligomerization partially explains the lowering of Aβ42 in Alzheimer's disease cerebrospinal fluid
Öppna denna publikation i ny flik eller fönster >>Oligomerization partially explains the lowering of Aβ42 in Alzheimer's disease cerebrospinal fluid
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2009 (Engelska)Ingår i: Neuro-degenerative diseases, ISSN 1660-2862, Vol. 6, nr 4, s. 139-147Artikel i tidskrift (Refereegranskat) 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.

Nyckelord
Alzheimer’s disease, CSF, Amyloid-β, oligomers
Nationell ämneskategori
Medicin och hälsovetenskap
Forskningsämne
Geriatrik
Identifikatorer
urn:nbn:se:uu:diva-98510 (URN)10.1159/000225376 (DOI)000269623400001 ()19521063 (PubMedID)
Tillgänglig från: 2009-02-24 Skapad: 2009-02-24 Senast uppdaterad: 2010-07-08Bibliografiskt granskad

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