The DOI matches its Crossref record; 82 of the 83 references it cites were found in a registry or an index.
Presenilin-1 P264L Knock-In Mutation: Differential Effects on Aβ Production, Amyloid Deposition, and Neuronal Vulnerability
Open accessAbstract
The pathogenic mechanism linking presenilin-1 (PS-1) gene mutations to familial Alzheimer's disease (FAD) is uncertain, but has been proposed to include increased neuronal sensitivity to degeneration and enhanced amyloidogenic processing of the β-amyloid precursor protein (APP). We investigated this issue by using gene targeting with the Cre-lox system to introduce an FAD-linked P264L mutation into the endogenous mouse PS-1 gene, an approach that maintains normal regulatory controls over expression. Primary cortical neurons derived from PS-1 homozygous mutant knock-in mice exhibit basal neurodegeneration similar to their PS-1 wild-type counterparts. Staurosporine and Aβ1–42 induce apoptosis, and neither the dose dependence nor maximal extent of cell death is altered by the PS-1 knock-in mutation. Similarly, glutamate-induced neuronal necrosis is unaffected by the PS-1P264L mutation. The lack of effect of the PS-1P264L mutation is confirmed by measures of basal- and toxin-induced caspase and calpain activation, biochemical indices of apoptotic and necrotic signaling, respectively. To analyze the influence of the PS-1P264L knock-in mutation on APP processing and the development of AD-type neuropathology, we created mouse lines carrying mutations in both PS-1 and APP. In contrast to the lack of effect on neuronal vulnerability, cortical neurons cultured from PS-1P264L homozygous mutant mice secrete Aβ42 at an increased rate, whereas secretion of Aβ40 is reduced. Moreover, the PS-1 knock-in mutation selectively increases Aβ42 levels in the mouse brain and accelerates the onset of amyloid deposition and its attendant reactive gliosis, even as a single mutant allele. We conclude that expression of an FAD-linked mutant PS-1 at normal levels does not generally increase cortical neuronal sensitivity to degeneration. Instead, enhanced amyloidogenic processing of APP likely is critical to the pathogenesis of PS-1-linked FAD.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“FAD mutations can even decrease secretion of the most abundantly released Aβ isoform, Aβ40, while still increasing the Aβ42 to Aβ40 ratio [90, 134, 173].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [173]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Thornberry, N. A., & Lazebnik, Y. A. (1998) · Science · doi:10.1126/science.281.5381.1312 · Cited by 6,857
Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice
Hsiao, K., Chapman, P., Nilsen, S., Eckman, C., Harigaya, Y., Younkin, S., Yang, F., & Cole, G. (1996) · Science · doi:10.1126/science.274.5284.99 · Cited by 4,210
Diffusible, nonfibrillar ligands derived from Aβ 1–42 are potent central nervous system neurotoxins
Lambert, M. P., Barlow, A. K., Chromy, B. A., Edwards, C., Freed, R., Liosatos, M., Morgan, T. E., Rozovsky, I., Trommer, B., Viola, K. L., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.11.6448 · Cited by 3,506
Scheuner, D., Eckman, C., Jensen, M., Song, X., Citron, M., Suzuki, N., Bird, T. D., Hardy, J., Hutton, M., Kukull, W., et al. (1996) · Nature Medicine · doi:10.1038/nm0896-864 · Cited by 2,599
Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein
Games, D., Adams, D., Alessandrini, R., Barbour, R., Borthelette, P., Blackwell, C., Carr, T., Clemens, J., Donaldson, T., Gillespie, F., et al. (1995) · Nature · doi:10.1038/373523a0 · Cited by 2,516
A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain
De Strooper, B., Annaert, W., Cupers, P., Saftig, P., Craessaerts, K., Mumm, J. S., Schroeter, E. H., Schrijvers, V., Wolfe, M. S., Ray, W. J., et al. (1999) · Nature · doi:10.1038/19083 · Cited by 2,100
Wolfe, M. S., Xia, W., Ostaszewski, B. L., Diehl, T. S., Kimberly, W. T., & Selkoe, D. J. (1999) · Nature · doi:10.1038/19077 · Cited by 1,959
Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein
De Strooper, B., Saftig, P., Craessaerts, K., Vanderstichele, H., Guhde, G., Annaert, W., Von Figura, K., & Van Leuven, F. (1998) · Nature · doi:10.1038/34910 · Cited by 1,818
Citron, M., Oltersdorf, T., Haass, C., McConlogue, L., Hung, A. Y., Seubert, P., Vigo-Pelfrey, C., Lieberburg, I., & Selkoe, D. J. (1992) · Nature · doi:10.1038/360672a0 · Cited by 1,757
Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology
Sturchler-Pierrat, C., Abramowski, D., Duke, M., Wiederhold, K.-H., Mistl, C., Rothacher, S., Ledermann, B., Bürki, K., Frey, P., Paganetti, P. A., et al. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.24.13287 · Cited by 1,507
Research works printed but not linked: 2
- Dorfman, 1998, Creation and characterization of two distinct types of mutations in PS-1 using gene targeting in mice., Soc Neurosci Abstr, 24, 472
- Siman R Durkin JT Husten EJ Savage MJ Murthy S Mistretta S Chatterjee S Rotella DP Dembofsky B Poorman R Greenberg BD (1995) Genesis and degradation of Aβ protein by cultured human neuroblastoma cells. in Research advances in Alzheimer's disease and related disorders, eds Iqbal K Mortimer J Winblad B Wisniewski H (Wiley, Sussex, UK), pp 675–684.
Cited by
Sorted by citations
GSK-3α regulates production of Alzheimer's disease amyloid-β peptides
Phiel, C. J., Wilson, C., Lee, V. M. ‐., & Klein, P. S. (2003) · Nature · doi:10.1038/nature01640 · Cited by 1,211
Aβ42‐driven cerebral amyloidosis in transgenic mice reveals early and robust pathology
Radde, R., Bolmont, T., Kaeser, S. A., Coomaraswamy, J., Lindau, D., Stoltze, L., Calhoun, M. E., Jäggi, F., Wolburg, H., Gengler, S., et al. (2006) · The EMBO Reports · doi:10.1038/sj.embor.7400784 · Cited by 986
Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease
Garcia-Alloza, M., Robbins, E. M., Zhang-Nunes, S. X., Purcell, S. M., Betensky, R. A., Raju, S., Prada, C., Greenberg, S. M., Bacskai, B. J., & Frosch, M. P. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2006.08.017 · Cited by 744
Shen, J., & Kelleher, R. J. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0608332104 · Cited by 485
Presenilins and -Secretase: Structure, Function, and Role in Alzheimer DiseasePreprint
Strooper, B. D., Iwatsubo, T., & Wolfe, M. S. (2011) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006304 · Cited by 490
Metadata
- Authors
- Siman, R., Reaume, A. G., Savage, M. J., Trusko, S., Lin, Y.-G., Scott, R. W., & Flood, D. G.
- Affiliations
- University of Pennsylvania (US)
- ORCID
- Reaume, Andrew G.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2000-12-01
- Volume
- 20
- Issue
- 23
- Pages
- 8717-8726
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6773081
- OpenAlex
- W1651448739
- Cited by
- 133
- References
- 83
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 3 · 2018: 2 · 2017: 3 · 2016: 2 · 2015: 4 · 2014: 2 · 2013: 10 · 2012: 4
- FWCI
- 3.06
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- presenilin 1, familial Alzheimer's disease, amyloid-beta production, amyloid-beta 42, amyloid deposition, neuronal vulnerability, cortical neurons, apoptosis, staurosporine, caspase activation, calpain, APP processing, reactive gliosis
- MeSH terms
- Alzheimer Disease, Amyloid, Animals, Calpain, Cell Survival, Cells, Cultured, Cerebral Cortex, Disease Models, Animal, Homozygote, Membrane Proteins, Mice, Mutant Strains, Mice, Transgenic, Neurons, Peptide Fragments, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Apoptosis, Gene Targeting, Glutamic Acid, Staurosporine, Amino Acid Substitution, Caspases, Mice, Presenilin-1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
