Several pathogenic Alzheimer's disease (AD) mutations have been described, all of which cause increased amyloid beta-protein (Abeta) levels. Here we present studies of a pathogenic amyloid precursor protein (APP) mutation, located within the Abeta sequence at codon 693 (E693G), that causes AD in a Swedish family. Carriers of this 'Arctic' mutation showed decreased Abeta42 and Abeta40 levels in plasma. Additionally, low levels of Abeta42 were detected in conditioned media from cells transfected with APPE693G. Fibrillization studies demonstrated no difference in fibrillization rate, but Abeta with the Arctic mutation formed protofibrils at a much higher rate and in larger quantities than wild-type (wt) Abeta. The finding of increased protofibril formation and decreased Abeta plasma levels in the Arctic AD may reflect an alternative pathogenic mechanism for AD involving rapid Abeta protofibril formation leading to accelerated buildup of insoluble Abeta intra- and/or extracellularly.
This study was aimed at investigating the consequences of Met-35 oxidation on the formation of small A peptide oligomers and also at attempting to find oxidation-mediated ratelimiting steps in the fibrillization cascade of the Met-35(O)-modified A-(1-40) peptide using a Fourier transform ion cyclotron resonance (FTICR) mass spectrometer and a homebuilt electrospray device. Electrospray ionization (ESI) mass spectrometry has been used previously to detect and characterize A peptides in vitro (16) as well as in vivo (17). Using gentle ESI conditions, small aggregates of A-(1-40) in water can be transferred to the gas phase and detected, making it possible to monitor the aggregation of A-(1-40) over time (16). The oligomer distribution detected by ESI mass spectrometry (16) is similar to that approached in the short irradiation time limit of photo-induced cross-linking experiments (18).
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.