Nature Neuroscience
4, 887 - 893 (2001)
Published online: 20 August 2001; | doi:10.1038/nn0901-887
The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced A protofibril formationCamilla Nilsberth1, Anita Westlind-Danielsson1, 2, Christopher B. Eckman3, Margaret M. Condron4, Karin Axelman1, Charlotte Forsell1, Charlotte Stenh1, Johan Luthman2, David B. Teplow4, Steven G. Younkin3, Jan Näslund1
& Lars Lannfelt11
Karolinska Institutet, Department of Neurotec, Geriatric Medicine, Novum KFC, S-141 86 Huddinge, Sweden
2
Bioscience, Discovery Research Area CNS & Pain Control, AstraZeneca, S-151 85 Södertälje, Sweden
3
Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, Florida 32224, USA
4
Center for Neurologic Diseases, Brigham & Women's Hospital, 77 Avenue Louis Pasteur (HIM756), Boston, Massachusetts 02115, USA
Correspondence should be addressed to Lars Lannfelt lars.lannfelt@neurotec.ki.seSeveral pathogenic Alzheimer's disease (AD) mutations have been described, all of which cause increased amyloid  -protein (A) levels. Here we present studies of a pathogenic amyloid precursor protein (APP) mutation, located within the A sequence at codon 693 (E693G), that causes AD in a Swedish family. Carriers of this 'Arctic' mutation showed decreased A42 and A40 levels in plasma. Additionally, low levels of A42 were detected in conditioned media from cells transfected with APPE693G. Fibrillization studies demonstrated no difference in fibrillization rate, but A with the Arctic mutation formed protofibrils at a much higher rate and in larger quantities than wild-type (wt) A. The finding of increased protofibril formation and decreased A plasma levels in the Arctic AD may reflect an alternative pathogenic mechanism for AD involving rapid A protofibril formation leading to accelerated buildup of insoluble A intra- and/or extracellularly.
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