Mutation of the β-amyloid precursor protein in familial Alzheimer's disease increases β-protein production
Abstract
Progressive cerebral deposition of the 39-43-amino-acid amyloid beta-protein (A beta) is an invariant feature of Alzheimer's disease which precedes symptoms of dementia by years or decades. The only specific molecular defects that cause Alzheimer's disease which have been identified so far are missense mutations in the gene encoding the beta-amyloid precursor protein (beta-APP) in certain families with an autosomal dominant form of the disease (familial Alzheimer's disease, or FAD). These mutations are located within or immediately flanking the A beta region of beta-APP, but the mechanism by which they cause the pathological phenotype of early and accelerated A beta deposition is unknown. Here we report that cultured cells which express a beta-APP complementary DNA bearing a double mutation (Lys to Asn at residue 595 plus Met to Leu at position 596) found in a Swedish FAD family produce approximately 6-8-fold more A beta than cells expressing normal beta-APP. The Met 596 to Leu mutation is principally responsible for the increase. These data establish a direct link between a FAD genotype and the clinicopathological phenotype. Further, they confirm the relevance of the continuous A beta production by cultured cells for elucidating the fundamental mechanism of Alzheimer's disease.
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In familial AD, metabolic effects of mutations promote increased levels of total Aβ, or increased Aβ42 to Aβ40 ratio, conditions that favor oligomerization.
“In FAD, metabolic effects of mutations promote increased levels of total Aβ, or increased Aβ42 to Aβ40 ratio (Borchelt et al., 1996; Citron et al., 1992), conditions that favor oligomerization.”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Citron et al., 1992
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- Authors
- Citron, M., Oltersdorf, T., Haass, C., McConlogue, L., Hung, A. Y., Seubert, P., Vigo-Pelfrey, C., Lieberburg, I., & Selkoe, D. J.
- Affiliations
- Brigham and Women's Hospital (US)
- Venue
- Nature
- Published
- 1992-12
- Volume
- 360
- Issue
- 6405
- Pages
- 672-674
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2090150925
- Cited by
- 1,757
- References
- 17
- Citations by year
- 2026: 19 · 2025: 19 · 2024: 28 · 2023: 24 · 2022: 33 · 2021: 39 · 2020: 37 · 2019: 43 · 2018: 41 · 2017: 39 · 2016: 50 · 2015: 37 · 2014: 59 · 2013: 45 · 2012: 59
- FWCI
- 52.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- 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
- familial Alzheimer's disease, amyloid precursor protein, APP mutations, genotype-phenotype correlation, amyloid deposition, cultured cells, autosomal dominant inheritance
- MeSH terms
- Alzheimer Disease, Amino Acid Sequence, Base Sequence, Cell Line, Humans, Kidney, Molecular Sequence Data, Mutation, Oligodeoxyribonucleotides, Sweden, Transfection, Restriction Mapping, Amyloid beta-Peptides, Amyloid beta-Protein Precursor
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