Pathogenic APP mutations near the gamma-secretase cleavage site differentially affect Abeta secretion and APP C-terminal fragment stability
Abstract
Release of amyloid beta (Abeta) from the amyloid precursor protein (APP) requires cleavages by beta- and gamma-secretases and plays a crucial role in Alzheimer's disease (AD) pathogenesis. Missense mutations in the APP gene causing familial AD are clustered around the beta-, alpha- and particular gamma-secretase cleavage sites. We systematically compare in primary neurons the effect on APP processing of a series of clinical APP mutations (two of which not characterized before) located in close proximity to the gamma-secretase cleavage site. We confirm and extend previous observations showing that all these mutations (T714I, V715M, V715A, I716V, V717I and V717L) affect gamma-secretase cleavage causing an increased relative ratio of Abeta42 to Abeta40. Taking advantage of these extended series of APP mutations we were able to demonstrate an inverse correlation between these ratios and the age at onset of the disease in the different families. In addition, a subset of mutations caused the accumulation of APP C-terminal fragments indicating that these mutations also influence the stability of APP C-terminal fragments. However, it is unlikely that these fragments contribute significantly to the disease process.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
Mutations in PS1 and PS2 primarily alter APP γ-cleavage, resulting in a decreased Aβ40/42 ratio.
“Mutations in PS1 and PS2 primarily alter APP γ-cleavage, thereby resulting in a decreased Aβ40/42 ratio.”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [38]
Cites
Alzheimer's disease: the amyloid cascade hypothesis
Hardy, J. A., & Higgins, G. A. (1992) · Science · doi:10.1126/science.1566067 · Cited by 7,484 · see citing works
Goate, A., Chartier-Harlin, M.-C., Mullan, M., Brown, J., Crawford, F., Fidani, L., Giuffra, L., Haynes, A., Irving, N., James, L., et al. (1991) · Nature · doi:10.1038/349704a0 · Cited by 4,659 · see citing works
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 · see citing works
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 1,913 · see citing works
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 · see citing works
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 · see citing works
Translating cell biology into therapeutic advances in Alzheimer's disease
Selkoe, D. J. (1999) · Nature · doi:10.1038/399a023 · Cited by 1,588 · see citing works
Mullan, M., Crawford, F., Axelman, K., Houlden, H., Lilius, L., Winblad, B., & Lannfelt, L. (1992) · Nature Genetics · doi:10.1038/ng0892-345 · Cited by 1,513 · see citing works
Suzuki, N., Cheung, T. T., Cai, X.-D., Odaka, A., Otvos, L., Eckman, C., Golde, T. E., & Younkin, S. G. (1994) · Science · doi:10.1126/science.8191290 · Cited by 1,471 · see citing works
Citron, M., Westaway, D., Xia, W., Carlson, G., Diehl, T., Levesque, G., Johnson-wood, K., Lee, M., Seubert, P., Davis, A., et al. (1997) · Nature Medicine · doi:10.1038/nm0197-67 · Cited by 1,271 · see citing works
Chartier-Harlin, M.-C., Crawford, F., Houlden, H., Warren, A., Hughes, D., Fidani, L., Goate, A., Rossor, M., Roques, P., Hardy, J., et al. (1991) · Nature · doi:10.1038/353844a0 · Cited by 1,214 · see citing works
Release of Excess Amyloid β Protein from a Mutant Amyloid β Protein Precursor
Cai, X.-D., Golde, T. E., & Younkin, S. G. (1993) · Science · doi:10.1126/science.8424174 · Cited by 913 · see citing works
Hendriks, L., van Duijn, C. M., Cras, P. P., Cruts, M., Hul, W. V., van Harskamp, F., Warren, A., McInnis, M. G., Antonarakis, S. E., Martin, J., et al. (1992) · Nature Genetics · doi:10.1038/ng0692-218 · Cited by 735 · see citing works
Haass, C., Hung, A. Y., Selkoe, D. J., & Teplow, D. B. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)32503-6 · Cited by 315 · see citing works
Annaert, W. G., Lévesque, L., Craessaerts, K., Dierinck, I., Snellings, G., Westaway, D. A., George‐Hyslop, P. S., Cordell, B., Fraser, P., & Strooper, B. D. (1999) · The Journal of Cell Biology · doi:10.1083/jcb.147.2.277 · Cited by 311 · see citing works
A New Pathogenic Mutation in the APP Gene (I716V) Increases the Relative Proportion of A 42(43)
Eckman, C. B., Mehta, N. D., Crook, R., Perez-tur, J., Prihar, G., Pfeiffer, E., Graff-Radford, N., Hinder, P., Yager, D., Zenk, B., et al. (1997) · Human Molecular Genetics · doi:10.1093/hmg/6.12.2087 · Cited by 236 · see citing works
Lichtenthaler, S. F., Wang, R., Grimm, H. S., Uljon, S., Masters, C. L., & Beyreuther, K. T. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.6.3053 · Cited by 231 · see citing works
Passer, B. J., Pellegrini, L., Russo, C., Siegel, R. M., Lenardo, M. J., Schettini, G., Bachmann, M. F., Tabaton, M., & D'adamio, L. (2000) · Journal of Alzheimer s Disease · doi:10.3233/jad-2000-23-408 · Cited by 207 · see citing works
Processing of β-Secretase by Furin and Other Members of the Proprotein Convertase Family
Creemers, J. W. M., Dominguez, D. I., Plets, E., Serneels, L., Taylor, N. A., Multhaup, G., Craessaerts, K., Annaert, W. G., & Strooper, B. D. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m006947200 · Cited by 187 · see citing works
Wang, R., Meschia, J. F., Cotter, R. J., & Sisodia, S. S. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)55397-7 · Cited by 178 · see citing works
Strooper, B. D., Simons, M., Multhaup, G., LEUVEN, F. V., Beyreuther, K. T., & Dotti, C. G. (1995) · The EMBO Journal · doi:10.1002/j.1460-2075.1995.tb00176.x · Cited by 176 · see citing works
Presenilin-1 differentially facilitates endoproteolysis of the β-amyloid precursor protein and Notch
Capell, A., Steiner, H., Romig, H., Keck, S., Baader, M., Grim, M. G., Baumeister, R., & Haass, C. (2000) · Nature Cell Biology · doi:10.1038/35008626 · Cited by 147 · see citing works
Barelli, H., Lebeau, A., Vizzavona, J., Delaère, P., Chevallier, N., Drouot, C., Marambaud, P., Ancolio, K., Buxbaum, J. D., Khorkova, O., et al. (1997) · Molecular Medicine · doi:10.1007/bf03401708 · Cited by 139 · see citing works
Pinnix, I., Musunuru, U., Tun, H. W., Sridharan, A., Golde, T. E., Eckman, C. B., Ziani‐Cherif, C., Onstead, L., & Sambamurti, K. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m005968200 · Cited by 138 · see citing works
Broeckhoven, C. V., Backhovens, H., Cruts, M., Martin, J. J., Crook, R., Houlden, H., & Hardy, J. (1994) · Neuroscience Letters · doi:10.1016/0304-3940(94)90385-9 · Cited by 126 · see citing works
Early-Onset Alzheimer Disease Caused by a New Mutation (V717L) in the Amyloid Precursor Protein Gene
Murrell, J. R., Hake, A. M., Quaid, K. A., Farlow, M. R., & Ghetti, B. F. (2000) · Archives of Neurology · doi:10.1001/archneur.57.6.885 · Cited by 111 · see citing works
Gillespie, S. L., Golde, T. E., & Younkin, S. G. (1992) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(92)90442-n · Cited by 107 · see citing works
Cell‐free assays for γ‐secretase activity
McLendon, C., Xin, T. A., Ziani‐Cherif, C., Murphy, M. P., Findlay, K. A., Lewis, P. A., Pinnix, I., Sambamurti, K., Wang, R., Fauq, A. H., et al. (2000) · The FASEB Journal · doi:10.1096/fj.00-0286fje · Cited by 106 · see citing works
Tamaoka, A., Kondo, T., Odaka, A., Sahara, N., Sawamura, N., Ozawa, K., Suzuki, N., Shoji, S., & Mori, H. (1994) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1994.2740 · Cited by 101 · see citing works
Increased Aβ42(43) from cell lines expressing presenilin 1 mutations
Mehta, N. D., Refolo, L. M., Eckman, C., Sanders, S., Yager, D., Perez‐Tur, J., Younkin, S., Duff, K., Hardy, J., & Hutton, M. (1998) · Annals of Neurology · doi:10.1002/ana.410430217 · Cited by 101 · see citing works
Nacmias, B., Latorraca, S., Piersanti, P., Forleo, P., Piacentini, S., Bracco, L., Amaducci, L. A., & Sorbi, S. (1995) · Neuroscience Letters · doi:10.1016/0304-3940(94)11100-w · Cited by 79 · see citing works
McPhie, D. L., Lee, R. K. K., Eckman, C. B., Olstein, D. H., Durham, S. P., Yager, D., Younkin, S. G., Wurtman, R. J., & Neve, R. L. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.40.24743 · Cited by 75 · see citing works
Secretion of the β‐Amyloid Precursor Proteina
Sisodia, S. S. (1992) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1992.tb27476.x · Cited by 53 · see citing works
Jonghe, C. D., Cras, P. P., Vanderstichele, H., Cruts, M., Vanderhoeven, I., Smouts, I., Vanmechelen, E., Martin, J.-J., Hendriks, L., & Broeckhoven, C. V. (1999) · Neurobiology of Disease · doi:10.1006/nbdi.1999.0247 · Cited by 45 · see citing works
APOE Genotype and Alzheimer´s Disease
(2000) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000017243 · Cited by 11 · see citing works
Solano (2000) · doi:10.1002/1531-8249(200002)47:2 · Cited by 3 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
Guo, T., Zhang, D., Zeng, Y., Huang, T. Y., Xu, H., & Zhao, Y. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00391-7 · Cited by 994 · see citing works
The road to restoring neural circuits for the treatment of Alzheimer's disease
Canter, R. G., Penney, J., & Tsai, L.-H. (2016) · Nature · doi:10.1038/nature20412 · Cited by 565 · see citing works
Nixon, R. A. (2017) · The FASEB Journal · doi:10.1096/fj.201700359 · Cited by 400 · see citing works
Muratore, C. R., Rice, H. C., Srikanth, P., Callahan, D. G., Shin, T., Benjamin, L. N. P., Walsh, D. M., Selkoe, D. J., & Young-Pearse, T. L. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu064 · Cited by 379 · see citing works
Genes associated with Alzheimer's disease: an overview and current status
Giri, M., Lü, Y., & Zhang, M. (2016) · Clinical Interventions in Aging · doi:10.2147/cia.s105769 · Cited by 311 · see citing works
Im, E., Jiang, Y., Stavrides, P. H., Darji, S., Erdjument-Bromage, H., Neubert, T. A., Choi, J. Y., Wegiel, J., Lee, J.-H., & Nixon, R. A. (2023) · Science Advances · doi:10.1126/sciadv.adg1925 · Cited by 80 · see citing works
Mutations in APP have independent effects on Aβ and CTFγ generation
Hecimovic, S., Wang, J., Dolios, G., Martinez, M., Wang, R., & Goate, A. M. (2004) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.04.018 · Cited by 70 · see citing works
Van Broeck, B., Vanhoutte, G., Pirici, D., Van Dam, D., Wils, H., Cuijt, I., Vennekens, K., Zabielski, M., Michalik, A., Theuns, J., et al. (2008) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.10.016 · Cited by 60 · see citing works
Covalent fragment inhibits intramembrane proteolysis
Eden, A., Zhao, J., Xiao, Y., Gibson, J., & Wang, C. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.958399 · Cited by 3 · see citing works
- Authors
- De Jonghe, C.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2001-08-01
- Volume
- 10
- Issue
- 16
- Pages
- 1665-1671
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2159237576
- Cited by
- 223
- References
- 36
- Citations by year
- 2026: 1 · 2025: 11 · 2024: 11 · 2023: 9 · 2022: 10 · 2021: 10 · 2020: 16 · 2019: 13 · 2018: 8 · 2017: 12 · 2016: 5 · 2015: 8 · 2014: 18 · 2013: 9 · 2012: 6
- FWCI
- 3.54
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fonds Wetenschappelijk Onderzoek
- Vlaamse regering
- 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 precursor protein, APP mutations, amyloid-beta secretion, Aβ42/Aβ40 ratio, APP C-terminal fragments, familial Alzheimer's disease, primary neurons, age of onset
- MeSH terms
- Animals, Binding Sites, Cells, Cultured, Electrophoresis, Polyacrylamide Gel, Humans, Mutation, Neurons, Peptide Fragments, Endopeptidases, Precipitin Tests, Transduction, Genetic, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Mice, Amyloid Precursor Protein Secretases
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