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The arctic mutation in the Abeta region of APP causes Alzheimers disease with increased Abeta protofibril formation and decreased Abeta peptide levels



The arctic mutation in the Abeta region of APP causes Alzheimers disease with increased Abeta protofibril formation and decreased Abeta peptide levels



Society for Neuroscience Abstracts 26(1-2): Abstract No -587 8



Several pathogenic Alzheimer's disease (AD) mutations have previously been described, all of which lead to increased amyloid beta-peptide (Abeta) levels. We have identified an AD-causing mutation located within the Abeta sequence at codon 693 (E693G) of the amyloid precursor protein. Surprisingly, carriers of this "Arctic" mutation showed decreased Abeta42 and Abeta40 levels in plasma. This finding was corroborated in vitro, where the Abeta42 concentration was low in conditioned media from cells transfected with APPE693G. Fibrillization studies demonstrated that Abeta peptides with the Arctic mutation formed protofibrils at a much higher rate and in larger quantities than wild-type (wt) Abeta. The unique finding of decreased Abeta plasma levels in the Arctic AD family highlights the complexity of the disease and is likely to reflect a novel pathogenic mechanism. We propose that this mechanism involves a rapid Abeta protofibril formation leading to accelerated build-up of insoluble Abeta intra- and/or extracellularly.

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