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An antibody against Amyloid-β protofibrils mediates their clearance and prevents amyloid formation in a mouse model of Alzheimer’s disease
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
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(English)Manuscript (Other (popular science, discussion, etc.))
Keyword [en]
Alzheimer’s disease, immunotherapy, monoclonal antibody, soluble amyloid-β, intraneuronal, transgenic mice
URN: urn:nbn:se:uu:diva-98581OAI: oai:DiVA.org:uu-98581DiVA: diva2:175087
Available from: 2009-02-26 Created: 2009-02-26 Last updated: 2010-01-14
In thesis
1. Targeting Early Stages of Alzheimer’s Disease in a Transgenic Model
Open this publication in new window or tab >>Targeting Early Stages of Alzheimer’s Disease in a Transgenic Model
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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 of insoluble Aβ. The early and persistent presence of protofibrils throughout Aβ amyloidosis makes them a promising target for future diagnostic and therapeutic strategies in AD.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 66 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 432
Research subject
urn:nbn:se:uu:diva-98584 (URN)978-91-554-7443-0 (ISBN)
Public defence
2009-04-16, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Available from: 2009-03-25 Created: 2009-02-26 Last updated: 2009-09-04Bibliographically approved

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