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The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Aβ protofibril formation

Nature Neuroscience volume 4, pages 887893 (2001) | Download Citation

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Abstract

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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Acknowledgements

We thank G. Arnerup, R. Kaiser, L. Lilius, S. Petrén and D. Yager for scientific support, and L. Tjernberg and colleagues in our department for comments on the manuscript. The following foundations are acknowledged: the Swedish Society for Medical Research, Trygg-Hansa, Stiftelsen för Gamla tjänarinnor, Åke Wibergs stiftelse, Erik Rönnbergs Stiftelse, Stiftelsen Clas Groschinskys minnesfond, Artur Eriksson, Gun & Bertil Stohnes stiftelse, Loo and Hans Ostermans stiftelse för geriatrisk forskning, Ulf Widengrens Minnesfond, Swedish Society for Medicine, the Alzheimer Foundation, the Swedish Medical Research Council (project 10819) and the US National Institutes of Health (grants NS38328 and AG14366 to D.B.T.).

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Affiliations

  1. Karolinska Institutet, Department of Neurotec, Geriatric Medicine, Novum KFC, S-141 86 Huddinge, Sweden

    • Camilla Nilsberth
    • , Anita Westlind-Danielsson
    • , Karin Axelman
    • , Charlotte Forsell
    • , Charlotte Stenh
    • , Jan Näslund
    •  & Lars Lannfelt
  2. Bioscience, Discovery Research Area CNS & Pain Control, AstraZeneca, S-151 85 Södertälje, Sweden

    • Anita Westlind-Danielsson
    •  & Johan Luthman
  3. Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, Florida 32224, USA

    • Christopher B. Eckman
    •  & Steven G. Younkin
  4. Center for Neurologic Diseases, Brigham & Women's Hospital, 77 Avenue Louis Pasteur (HIM756), Boston, Massachusetts 02115, USA

    • Margaret M. Condron
    •  & David B. Teplow

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Correspondence to Lars Lannfelt.

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https://doi.org/10.1038/nn0901-887

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