Familial Alzheimer's Disease–Linked Presenilin 1 Variants Elevate Aβ1–42/1–40 Ratio In Vitro and In Vivo
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Mutations in the presenilin 1 (PS1) and presenilin 2 genes cosegregate with the majority of early-onset familial Alzheimer's disease (FAD) pedigrees. We now document that the Abeta1-42(43)/Abeta1-40 ratio in the conditioned media of independent N2a cell lines expressing three FAD-linked PS1 variants is uniformly elevated relative to cells expressing similar levels of wild-type PS1. Similarly, the Abeta1-42(43)/Abeta1-40 ratio is elevated in the brains of young transgenic animals coexpressing a chimeric amyloid precursor protein (APP) and an FAD-linked PS1 variant compared with brains of transgenic mice expressing APP alone or transgenic mice coexpressing wild-type human PS1 and APP. These studies provide compelling support for the view that one mechanism by which these mutant PS1 cause AD is by increasing the extracellular concentration of Abeta peptides terminating at 42(43), species that foster Abeta deposition.
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Each genetic form of Alzheimer's disease either selectively increases the extracellular concentration of Aβ42 or increases both Aβ42 and Aβ40.
“each of these genetic forms of AD either selectively increases the extracellular concentration of A42 (Suzuki et al., 1994;Borchelt et al., 1996;Duff et al., 1996;Scheuner et al., 1996;Citron et al., 1997) or increases both 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 Borchelt et al., 1996
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 Borchelt et al., 1996
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- Authors
- Borchelt, D. R., Thinakaran, G., Eckman, C. B., Lee, M. K., Davenport, F., Ratovitsky, T., Prada, C.-M., Kim, G., Seekins, S., Yager, D., Slunt, H. H., Wang, R., Seeger, M., Levey, A. I., Gandy, S. E., Copeland, N. G., Jenkins, N. A., Price, D. L., Younkin, S. G., & Sisodia, S. S.
- Affiliations
- Johns Hopkins University (US)
- Mayo Clinic in Florida (US)
- Rockefeller University (US)
- Cornell University (US)
- Emory University (US)
- Frederick National Laboratory for Cancer Research (US)
- Corresponding author
- Sisodia, Sangram S.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 1996-11
- Volume
- 17
- Issue
- 5
- Pages
- 1005-1013
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2095745901
- Cited by
- 1,478
- References
- 40
- Citations by year
- 2026: 2 · 2025: 20 · 2024: 28 · 2023: 23 · 2022: 26 · 2021: 32 · 2020: 45 · 2019: 27 · 2018: 26 · 2017: 51 · 2016: 47 · 2015: 43 · 2014: 42 · 2013: 43 · 2012: 53
- FWCI
- 53.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neuron (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG05689, P50AG005146, F32AG005689, AG 05146)
- National Institute of Neurological Disorders and Stroke (NS-20471)
- 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, presenilin 1, PS1 mutations, amyloid-beta 42, amyloid precursor protein, transgenic mice, N2a cells, conditioned medium, amyloid deposition
- MeSH terms
- Alzheimer Disease, Animals, Brain Chemistry, Humans, Membrane Proteins, Mice, Transgenic, Mutation, Neuroblastoma, Recombinant Fusion Proteins, Transfection, Tumor Cells, Cultured, Gene Expression, Amyloid beta-Protein Precursor, Culture Media, Conditioned, Mice, Presenilin-1
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