Several pathogenic Alzheimer's disease (AD) mutations have been described, all of which cause increased amyloid β-protein (Aβ) levels. Here we present studies of a pathogenic amyloid precursor protein (APP) mutation, located within the Aβ sequence at codon 693 (E693G), that causes AD in a Swedish family. Carriers of this 'Arctic' mutation showed decreased Aβ42 and Aβ40 levels in plasma. Additionally, low levels of Aβ42 were detected in conditioned media from cells transfected with APPE693G. Fibrillization studies demonstrated no difference in fibrillization rate, but Aβ with the Arctic mutation formed protofibrils at a much higher rate and in larger quantities than wild-type (wt) Aβ. The finding of increased protofibril formation and decreased Aβ plasma levels in the Arctic AD may reflect an alternative pathogenic mechanism for AD involving rapid Aβ protofibril formation leading to accelerated buildup of insoluble Aβ intra- and/or extracellularly.
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