Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation.
Open accessAbstract
The 39- to 43-amino acid amyloid beta-protein (A beta), which is progressively deposited in cerebral plaques and blood vessels in Alzheimer disease (AD), is secreted by cultured human cells during normal metabolism. In studies of cell lines transfected with beta-amyloid precursor protein (beta APP) cDNAs, the beta APP mutation K670N/M671L found in a Swedish familial AD (FAD) pedigree has previously been shown to cause a marked augmentation of A beta secretion. Here, we have conducted blinded analyses of beta APP metabolism in primary skin fibroblasts from affected members of the Swedish FAD pedigree and their unaffected siblings or spouses. These fibroblasts continuously secrete a homogenous population of A beta molecules starting at Asp-1 (D672 of beta APP). We found a consistent and significant approximately 3-fold elevation of A beta release from all biopsied skin fibroblasts bearing the FAD mutation. No significant alterations of other metabolic derivatives of beta APP were detected. The elevated A beta levels were found in cells from both patients with clinical AD and presymptomatic subjects. Thus, A beta overproduction in this FAD pedigree is not a secondary event but is consistent with a causal role in the development of the disease. Increased A beta secretion can begin many years prior to onset of symptoms, even in peripheral tissues, indicating that it does not require preexisting neural abnormalities.
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The Swedish mutation causes concomitant increases in secreted Aβ42 and Aβ40.
“It is well established that this mutation causes concomitant increases in secreted A42 and A40 (Cai et al., 1993;Citron et al., 1994;Scheuner et al., 1996).”
From Age-Dependent Changes in Brain, CSF, and Plasma Amyloid β Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease (2001) · cites this paper as Citron et al., 1994
Secreted Aβ is readily detected in CSF, plasma, and medium conditioned by a wide variety of cultured cells.
“Secreted A is readily detected in CSF, plasma, and in medium conditioned by a wide variety of cultured cells”
From Age-Dependent Changes in Brain, CSF, and Plasma Amyloid β Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease (2001) · cites this paper as Citron et al., 1994
APP mutations occurring near the β-secretase cleavage site, such as the Swedish mutation (K670N/M671L), appear to result in increased production of total Aβ.
“mutations occurring near the βsecretase cleavage site, such as the Swedish mutation (K670N/M671L), appear to result in increased production of total Aβ [34, 35].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [35]
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“APP695 swd cells harbor the APP Swedish mutation (K670N/M671L), which increases β-secretase cleavage, resulting in elevated levels of Aβ secretion [53].”
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- Authors
- Citron, M., Vigo-Pelfrey, C., Teplow, D. B., Miller, C., Schenk, D., Johnston, J., Winblad, B., Venizelos, N., Lannfelt, L., & Selkoe, D. J.
- Affiliations
- Harvard University (US)
- Department of Neurology, Harvard Medical School, Boston, MA.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1994-12-06
- Volume
- 91
- Issue
- 25
- Pages
- 11993-11997
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC45362
- OpenAlex
- W1986695958
- Cited by
- 366
- References
- 8
- Citations by year
- 2026: 3 · 2025: 15 · 2024: 19 · 2023: 11 · 2022: 14 · 2021: 12 · 2020: 18 · 2019: 10 · 2018: 8 · 2017: 8 · 2016: 10 · 2015: 7 · 2014: 8 · 2013: 5 · 2012: 6
- FWCI
- 16.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r35ag007911-04)
- National Institute on Aging (AG-06173, AG-07911)
- 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
- amyloid-beta, amyloid precursor protein, dermal fibroblasts, Alzheimer disease pathogenesis
- MeSH terms
- Alzheimer Disease, Cell Line, Cells, Cultured, Embryo, Mammalian, Enzyme-Linked Immunosorbent Assay, Fibroblasts, Genotype, Humans, Kidney, Methionine, Phenylalanine, Skin, Sulfur Radioisotopes, Sweden, Tritium, Amyloid beta-Peptides, Point Mutation
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