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The Swedish mutation causes early-onset Alzheimer's disease by β-secretase cleavage within the secretory pathway

Nature Medicine volume 1, pages 1291–1296 (1995)Cite this article

Abstract

Several missense mutations causing early-onset Alzheimer's disease (AD) have been described in the gene coding for the β-amyloid precursor protein (βAPP). A double mutation found in a Swedish family is located before the amyloid β-peptide (Aβ) region of βAPP and results in the increased production and secretion of Aβ. Here we show that the increased production of Aβ results from a cellular mechanism, which differs substantially from that responsible for the production of Aβ from wild-type βAPP. in the latter case, Aβ generation requires reinternalization and recycling of βAPP. In the case of the Swedish mutation the N-terminal β-secretase cleavage of Aβ occurs in Golgi-derived vesicles, most likely within secretory vesicles. Therefore, this cleavage occurs in the same compartment as the α-secretase cleavage, which normally prevents Aβ production, explaining the increased Aβ generation by a competition between α and β-secretase.

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Authors and Affiliations

  1. Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital Boston, Massachusetts, 02115, USA

    Christian Haass, Cynthia A. Lemere, Anja Capell, Martin Citron & Dennis J. Selkoe

  2. Central Institute of Mental Health (University of Heidelberg), Department of Molecular Biology, J5, 68159, Mannheim, Germany

    Christian Haass & Anja Capell

  3. Athena Neurosciences Inc., South San Francisco, California, 94080, USA

    Peter Seubert & Dale Schenk

  4. Karolinska Institute, Department of Geriatric Medicine, B56, Huddinge S-141 86, Sweden

    Lars Lannfelt

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  1. Christian Haass
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  2. Cynthia A. Lemere
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  3. Anja Capell
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  4. Martin Citron
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  6. Dale Schenk
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  7. Lars Lannfelt
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  8. Dennis J. Selkoe
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Haass, C., Lemere, C., Capell, A. et al. The Swedish mutation causes early-onset Alzheimer's disease by β-secretase cleavage within the secretory pathway. Nat Med 1, 1291–1296 (1995). https://doi.org/10.1038/nm1295-1291

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