Targeting Early Stages of Alzheimer’s Disease in a Transgenic Model
The Arctic mutation causes early-onset Alzheimer’s disease (AD), and makes amyloid-β (Aβ) peptides more prone to form Aβ protofibrils. The aims of this thesis were to investigate the mechanisms of the Arctic mutation in vivo, and to use transgenic models to determine the role of early intermediates...
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Uppsala universitet, Institutionen för folkhälso- och vårdvetenskap
2009
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ftuppsalauniv:oai:DiVA.org:uu-98584 2023-05-15T14:48:22+02:00 Targeting Early Stages of Alzheimer’s Disease in a Transgenic Model Lord, Anna 2009 application/pdf http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-98584 eng eng Uppsala universitet, Institutionen för folkhälso- och vårdvetenskap Uppsala : Acta Universitatis Upsaliensis Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 432 http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-98584 urn:isbn:978-91-554-7443-0 info:eu-repo/semantics/openAccess Doctoral thesis, comprehensive summary info:eu-repo/semantics/doctoralThesis text 2009 ftuppsalauniv 2023-02-23T21:43:42Z The Arctic mutation causes early-onset Alzheimer’s disease (AD), and makes amyloid-β (Aβ) peptides more prone to form Aβ protofibrils. The aims of this thesis were to investigate the mechanisms of the Arctic mutation in vivo, and to use transgenic models to determine the role of early intermediates of Aβ aggregation, like protofibrils, in the pathogenesis. In addition, we aimed to evaluate protofibrils as a therapeutic target. Transgenic models with Arctic and Swedish mutations (tg-ArcSwe), and with the Swedish mutation alone (tg-Swe) were created. The Arctic mutation favored amyloidogenic processing of amyloid-β precursor protein (APP) in transgenic mice and cultured cells. The observed shift in the subcellular location and processing of APP led to increased production of intracellular Aβ in vitro, and also partly explained the early accumulation of intraneuronal Aβ in tg-ArcSwe mice. The intraneuronal Aβ in combination with enhanced levels of protofibrils appeared long before extracellular plaques emerged. Elevated protofibril levels were associated with intraneuronal Aβ and linked to spatial learning deficits in young mice, suggesting that protofibrils cause AD-related cognitive deficits. The Arctic mutation also enhanced senile plaque pathology in aged tg-ArcSwe mice, and the accelerated plaque deposition was accompanied by decreased intraneuronal Aβ. This suggests a dynamic equilibrium between the early accumulation of intraneuronal Aβ and the later senile plaque pathology. Aβ protofibrils were evaluated as a therapeutic target in tg-ArcSwe mice with passive immunization using a protofibril-selective antibody. This treatment cleared protofibrils without removing senile plaques. However, plaque formation was prevented if treatment began early, indicating that protofibrils are intermediate species of Aβ fibrillization in vivo. Targeting senile plaques with immunotherapy requires early diagnosis and intervention, whereas protofibrils can be specifically cleared from brain despite substantial AD-like deposition ... Doctoral or Postdoctoral Thesis Arctic Uppsala University: Publications (DiVA) Arctic |
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Uppsala University: Publications (DiVA) |
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ftuppsalauniv |
language |
English |
description |
The Arctic mutation causes early-onset Alzheimer’s disease (AD), and makes amyloid-β (Aβ) peptides more prone to form Aβ protofibrils. The aims of this thesis were to investigate the mechanisms of the Arctic mutation in vivo, and to use transgenic models to determine the role of early intermediates of Aβ aggregation, like protofibrils, in the pathogenesis. In addition, we aimed to evaluate protofibrils as a therapeutic target. Transgenic models with Arctic and Swedish mutations (tg-ArcSwe), and with the Swedish mutation alone (tg-Swe) were created. The Arctic mutation favored amyloidogenic processing of amyloid-β precursor protein (APP) in transgenic mice and cultured cells. The observed shift in the subcellular location and processing of APP led to increased production of intracellular Aβ in vitro, and also partly explained the early accumulation of intraneuronal Aβ in tg-ArcSwe mice. The intraneuronal Aβ in combination with enhanced levels of protofibrils appeared long before extracellular plaques emerged. Elevated protofibril levels were associated with intraneuronal Aβ and linked to spatial learning deficits in young mice, suggesting that protofibrils cause AD-related cognitive deficits. The Arctic mutation also enhanced senile plaque pathology in aged tg-ArcSwe mice, and the accelerated plaque deposition was accompanied by decreased intraneuronal Aβ. This suggests a dynamic equilibrium between the early accumulation of intraneuronal Aβ and the later senile plaque pathology. Aβ protofibrils were evaluated as a therapeutic target in tg-ArcSwe mice with passive immunization using a protofibril-selective antibody. This treatment cleared protofibrils without removing senile plaques. However, plaque formation was prevented if treatment began early, indicating that protofibrils are intermediate species of Aβ fibrillization in vivo. Targeting senile plaques with immunotherapy requires early diagnosis and intervention, whereas protofibrils can be specifically cleared from brain despite substantial AD-like deposition ... |
format |
Doctoral or Postdoctoral Thesis |
author |
Lord, Anna |
spellingShingle |
Lord, Anna Targeting Early Stages of Alzheimer’s Disease in a Transgenic Model |
author_facet |
Lord, Anna |
author_sort |
Lord, Anna |
title |
Targeting Early Stages of Alzheimer’s Disease in a Transgenic Model |
title_short |
Targeting Early Stages of Alzheimer’s Disease in a Transgenic Model |
title_full |
Targeting Early Stages of Alzheimer’s Disease in a Transgenic Model |
title_fullStr |
Targeting Early Stages of Alzheimer’s Disease in a Transgenic Model |
title_full_unstemmed |
Targeting Early Stages of Alzheimer’s Disease in a Transgenic Model |
title_sort |
targeting early stages of alzheimer’s disease in a transgenic model |
publisher |
Uppsala universitet, Institutionen för folkhälso- och vårdvetenskap |
publishDate |
2009 |
url |
http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-98584 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_relation |
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 432 http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-98584 urn:isbn:978-91-554-7443-0 |
op_rights |
info:eu-repo/semantics/openAccess |
_version_ |
1766319451073937408 |