Cited by 598Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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

Haass, Christian, Lemere, Cynthia A., Capell, Anja, Citron, Martin, Seubert, Peter, Schenk, Dale, Lannfelt, Lars, Selkoe, Dennis J.·1995·Nature Medicine

Abstract

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

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Crossref · 10.1038/nm1295-1291

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Authors
Haass, C., Lemere, C. A., Capell, A., Citron, M., Seubert, P., Schenk, D., Lannfelt, L., & Selkoe, D. J.
Affiliations
  • Brigham and Women's Hospital (US)
  • Karolinska Institutet (SE)
Venue
Nature Medicine
Published
1995-12
Volume
1
Issue
12
Pages
1291-1296
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
OpenAlex
W2034504333
Cited by
592
References
33
Citations by year
2026: 20 · 2025: 14 · 2024: 24 · 2023: 28 · 2022: 19 · 2021: 27 · 2020: 13 · 2019: 23 · 2018: 11 · 2017: 18 · 2016: 21 · 2015: 19 · 2014: 21 · 2013: 29 · 2012: 30
FWCI
12.81
Type
journal article
Language
en
Open access
closed
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute on Aging (AG 12749, AG-06173, R01AG012749)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Swedish mutation, early-onset Alzheimer's disease, amyloid precursor protein, alpha-secretase, Golgi-derived vesicles, secretory pathway, secretory vesicles
MeSH terms
Aged, Alzheimer Disease, Amino Acid Sequence, Brain, Golgi Apparatus, Humans, Molecular Sequence Data, Mutation, Endopeptidases, Sweden, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Age of Onset, Amyloid Precursor Protein Secretases

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