Targeting Early Stages of Alzheimer’s Disease in a Transgenic Model

University dissertation from Uppsala : Acta Universitatis Upsaliensis

Author: Anna Lord; Uppsala Universitet.; [2009]

Keywords: Geriatrics; geriatrik;

Abstract: The Arctic mutation causes early-onset Alzheimer’s disease (AD), and makes amyloid-? (A?) peptides more prone to form A? 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 A? 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-? 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 A? in vitro, and also partly explained the early accumulation of intraneuronal A? in tg-ArcSwe mice. The intraneuronal A? in combination with enhanced levels of protofibrils appeared long before extracellular plaques emerged. Elevated protofibril levels were associated with intraneuronal A? 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 A?. This suggests a dynamic equilibrium between the early accumulation of intraneuronal A? and the later senile plaque pathology.A? 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 A? 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 A?. The early and persistent presence of protofibrils throughout A? amyloidosis makes them a promising target for future diagnostic and therapeutic strategies in AD.

  CLICK HERE TO DOWNLOAD THE WHOLE DISSERTATION. (in PDF format)