The DOI matches its Crossref record; 55 of the 56 references it cites were found in a registry or an index, and 1 are not checked yet.
ADAM10 is the physiologically relevant, constitutive α‐secretase of the amyloid precursor protein in primary neurons
Open accessAbstract
The amyloid precursor protein (APP) undergoes constitutive shedding by a protease activity called alpha-secretase. This is considered an important mechanism preventing the generation of the Alzheimer's disease amyloid-beta peptide (Abeta). alpha-Secretase appears to be a metalloprotease of the ADAM family, but its identity remains to be established. Using a novel alpha-secretase-cleavage site-specific antibody, we found that RNAi-mediated knockdown of ADAM10, but surprisingly not of ADAM9 or 17, completely suppressed APP alpha-secretase cleavage in different cell lines and in primary murine neurons. Other proteases were not able to compensate for this loss of alpha-cleavage. This finding was further confirmed by mass-spectrometric detection of APP-cleavage fragments. Surprisingly, in different cell lines, the reduction of alpha-secretase cleavage was not paralleled by a corresponding increase in the Abeta-generating beta-secretase cleavage, revealing that both proteases do not always compete for APP as a substrate. Instead, our data suggest a novel pathway for APP processing, in which ADAM10 can partially compete with gamma-secretase for the cleavage of a C-terminal APP fragment generated by beta-secretase. We conclude that ADAM10 is the physiologically relevant, constitutive alpha-secretase of APP.
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“these observations support the model that GDE2 is required to control neuronal ADAM10 α-secretase activity.”
From GDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein (2021) · cites this paper as [3]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“ADAM10 cleaves APP to generate neuroprotective soluble APPα (sAPPα), which precludes the generation of Aβ”
From GDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein (2021) · cites this paper as [3]
The cited source says what the claim attributes to it.
In the citing paper
“genetic ablation and knockdown studies identify ADAM10 as the major α-secretase that cleaves APP in neurons (3, 4).”
From GDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein (2021) · cites this paper as [3]
The cited source says what the claim attributes to it.
In the citing paper
“ADAM10 cleaves APP to generate neuroprotective soluble APPα (sAPPα), which precludes the generation of Aβ”
From GDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein (2021) · cites this paper as [3]
In the citing paper
“has a major role in the shedding of β-amyloid protein, therefore possessing the ability to prevent the generation of the pathogenic Aβ peptide in Alzheimer's disease.53,54”
From Canonical Wnt pathway and the LDL receptor superfamily in neuronal cholesterol homeostasis and function (2024) · cites this paper as [54]
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
1 retracted
RETRACTED ARTICLE: APP binds DR6 to trigger axon pruning and neuron death via distinct caspases
Nikolaev, A., McLaughlin, T., O’Leary, D. D. M., & Tessier-Lavigne, M. (2009) · Nature · doi:10.1038/nature07767 · Cited by 992
RetractedVassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., Denis, P., Teplow, D. B., Ross, S., Amarante, P., Loeloff, R., et al. (1999) · Science · doi:10.1126/science.286.5440.735 · Cited by 3,876
Expression profiling reveals off-target gene regulation by RNAi
Jackson, A. L., Bartz, S. R., Schelter, J., Kobayashi, S. V., Burchard, J., Mao, M., Li, B., Cavet, G., & Linsley, P. S. (2003) · Nature Biotechnology · doi:10.1038/nbt831 · Cited by 2,370
Cleavage of Amyloid β Peptide During Constitutive Processing of Its Precursor
Esch, F. S., Keim, P. S., Beattie, E. C., Blacher, R. W., Culwell, A. R., Oltersdorf, T., McClure, D., & Ward, P. J. (1990) · Science · doi:10.1126/science.2111583 · Cited by 1,403
Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands
Şahin, U., Weskamp, G., Kelly, K., Zhou, H., Higashiyama, S., Peschon, J. J., Hartmann, D., Säftig, P., & Blobel, C. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200307137 · Cited by 1,013
Lammich, S., Kojro, E., Postina, R., Gilbert, S., Pfeiffer, R., Jasionowski, M., Haass, C., & Fahrenholz, F. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.7.3922 · Cited by 975
Buxbaum, J. D., Liu, K.-N., Luo, Y., Slack, J. L., Stocking, K. L., Peschon, J. J., Johnson, R. S., Castner, B. J., Cerretti, D. P., & Black, R. A. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.43.27765 · Cited by 952
Evidence that production and release of amyloid beta-protein involves the endocytic pathway
Koo, E. H., & Squazzo, S. L. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)32449-3 · Cited by 829
Alzheimer's Disease: Molecular Understanding Predicts Amyloid-Based Therapeutics
Selkoe, D. J., & Schenk, D. (2003) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.43.100901.140248 · Cited by 829
Beta-amyloid precursor protein cleavage by a membrane-bound protease.
Sisodia, S. S. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.13.6075 · Cited by 738
Control of Peripheral Nerve Myelination by the ß-Secretase BACE1
Willem, M., Garratt, A. N., Novak, B., Citron, M., Kaufmann, S., Rittger, A., DeStrooper, B., Saftig, P., Birchmeier, C., & Haass, C. (2006) · Science · doi:10.1126/science.1132341 · Cited by 703
Hartmann, D. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.21.2615 · Cited by 680
Postina, R., Schroeder, A., Dewachter, I., Bohl, J., Schmitt, U., Kojro, E., Prinzen, C., Endres, K., Hiemke, C., Blessing, M., et al. (2004) · Journal of Clinical Investigation · doi:10.1172/jci20864 · Cited by 638
Haass, C., Lemere, C. A., Capell, A., Citron, M., Seubert, P., Schenk, D., Lannfelt, L., & Selkoe, D. J. (1995) · Nature Medicine · doi:10.1038/nm1295-1291 · Cited by 592
Take five—BACE and the γ‐secretase quartet conduct Alzheimer's amyloid β‐peptide generation
Haass, C. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600061 · Cited by 547
ADAM10 cleavage of N‐cadherin and regulation of cell–cell adhesion and β‐catenin nuclear signalling
Reiß, K., Maretzky, T., Ludwig, A., Tousseyn, T., Strooper, B. D., Hartmann, D., & Säftig, P. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600548 · Cited by 481
Sastre, M., Steiner, H., Fuchs, K. P., Capell, A., Multhaup, G., Condron, M. M., Teplow, D. B., & Haass, C. (2001) · EMBO Reports · doi:10.1093/embo-reports/kve180 · Cited by 472
Reiß, K., & Säftig, P. (2008) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2008.11.002 · Cited by 419
Furukawa, K., Sopher, B. L., Rydel, R. E., Begley, J. G., Pham, D. G., Martin, G. M., Fox, M., & Mattson, M. P. (1996) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1996.67051882.x · Cited by 414
Méziane, H., Dodart, J., Mathis, C., Little, S. H., Clemens, J. A., Paul, S. M., & Ungerer, A. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.21.12683 · Cited by 379
Skovronsky, D., Moore, D. B., Milla, M. E., Doms, R. W., & Lee, V. M. ‐. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.4.2568 · Cited by 325
Metalloprotease-Disintegrin MDC9: Intracellular Maturation and Catalytic Activity
Roghani, M., Becherer, J. D., Moss, M. L., Atherton, R. E., Erdjument‐Bromage, H., Arribas, J., Blackburn, K., Weskamp, G., Tempst, P., & Blobel, C. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.6.3531 · Cited by 324
Selective Use of ADAM10 and ADAM17 in Activation of Notch1 Signaling
Çağavi, E., & Weinmaster, G. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.00406-09 · Cited by 309
Putative function of ADAM9, ADAM10, and ADAM17 as APP -secretase
Asai, M., Hattori, C., Szabó, B., Sasagawa, N., Maruyama, K., Tanuma, S.-I., & Ishiura, S. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(02)02999-6 · Cited by 303
KOIKE, H., Tomioka, S., Sorimachi, H., Saido, T. C., Maruyama, K., Okuyama, A., Fujisawa‐Sehara, A., Ohno, S., Suzuki, K., & Ishiura, S. (1999) · Biochemical Journal · doi:10.1042/bj3430371 · Cited by 290
Stein, T. D., Anders, N. J., DeCarli, C. S., Chan, S. L., Mattson, M. P., & Johnson, J. A. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.2211-04.2004 · Cited by 286
Metalloprotease ADAM10 Is Required for Notch1 Site 2 Cleavage
van Tetering, G., van Diest, P. J., Verlaan-Klink, I., van der Wall, E., Kopan, R., & Vooijs, M. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.006775 · Cited by 274
Stachel, S. J., Coburn, C. A., Steele, T. G., Jones, K. G., Loutzenhiser, E. F., Gregro, A. R., Rajapakse, H. A., Lai, M.-T., Crouthamel, M.-C., Xu, M., et al. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm049379g · Cited by 262
Gall, S. M. L., Bobé, P., Reiß, K., Horiuchi, K., Niu, X. D., Lundell, D. J., Gibb, D. R., Conrad, D. H., Säftig, P., & Blobel, C. (2009) · Molecular Biology of the Cell · doi:10.1091/mbc.e08-11-1135 · Cited by 250
Pruessmeyer, J., & Ludwig, A. (2008) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2008.09.005 · Cited by 248
Kim, M., Suh, J., Romano, D., Truong, M. H., Mullin, K., Hooli, B., Norton, D., Tesco, G., Elliott, K., Wagner, S. L., et al. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp323 · Cited by 234
Weskamp, G., Cai, H., Brodie, T. A., Higashyama, S., Manova, K., Ludwig, T. E., & Blobel, C. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.5.1537-1544.2002 · Cited by 215
ADAM10 is a principal 'sheddase' of the low-affinity immunoglobulin E receptor CD23
Weskamp, G., Ford, J. W., Sturgill, J., Martin, S. L., Docherty, A., Swendeman, S. L., BROADWAY, N. M., Hartmann, D., Säftig, P., Umland, S. P., et al. (2006) · Nature Immunology · doi:10.1038/ni1399 · Cited by 213
Sennvik, K., Fastbom, J., Blomberg, M. E., Wahlund, L., Winblad, B., & Benedikz, E. (2000) · Neuroscience Letters · doi:10.1016/s0304-3940(99)00929-5 · Cited by 193
Active-site determinants of substrate recognition by the metalloproteinases TACE and ADAM10
Caescu, C. I., Jeschke, G. R., & Turk, B. E. (2009) · Biochemical Journal · doi:10.1042/bj20090549 · Cited by 179
A novel pathway for amyloid precursor protein processing
Portelius, E., Price, E. A., Brinkmalm, G., Stiteler, M., Olsson, M., Persson, R., Brinkmalm, A., Zetterberg, H., Simon, A. J., & Blennow, K. (2009) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2009.06.002 · Cited by 169
Page, R. M., Baumann, K., Tomioka, M., Pérez‐Revuelta, B. I., Fukumori, A., Jacobsen, H., Flohr, A., Luebbers, T., Ozmen, L., Steiner, H., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m708754200 · Cited by 165
Slack, B. E., Leona, K., & Seah, C. C. (2001) · Biochemical Journal · doi:10.1042/0264-6021:3570787 · Cited by 164
Cupers, P., Bentahir, M., Craessaerts, K., Orlans, I., Vanderstichele, H., Säftig, P., Strooper, B. D., & Annaert, W. G. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.200104045 · Cited by 162
Role of ADAMs in the Ectodomain Shedding and Conformational Conversion of the Prion Protein
Taylor, D. R., Parkin, E. T., Cocklin, S. L., Ault, J. R., Ashcroft, A. E., Turner, A. J., & Hooper, N. M. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.032599 · Cited by 144
Simons, M., de Strooper, B., Multhaup, G., Tienari, P., Dotti, C., & Beyreuther, K. (1996) · The Journal of Neuroscience · doi:10.1523/jneurosci.16-03-00899.1996 · Cited by 131
P2Y2 Nucleotide Receptors Enhance α-Secretase-dependent Amyloid Precursor Protein Processing
Camden, J. M., Schrader, A. M., Camden, R. E., González, F. A., Erb, L., Seye, C. I., & Weisman, G. A. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m500219200 · Cited by 125
Kojro, E., Postina, R., Buro, C., Meiringer, C., Gehrig‐Burger, K., & Fahrenholz, F. (2006) · The FASEB Journal · doi:10.1096/fj.05-4812fje · Cited by 118
Alpha-Secretase As a Therapeutic Target
Fahrenholz, F. (2007) · Current Alzheimer Research · doi:10.2174/156720507781788837 · Cited by 111
Slack, B. E., Leona, K., & Seah, C. C. (2001) · Biochemical Journal · doi:10.1042/bj3570787 · Cited by 102
Bandyopadhyay, S., Goldstein, L. E., Lahiri, D. K., & Rogers, J. T. (2007) · Current Medicinal Chemistry · doi:10.2174/092986707782360060 · Cited by 95
Allinson, T. M. J., Parkin, E. T., Condon, T. P., Schwager, S. L. U., Sturrock, E. D., Turner, A. J., & Hooper, N. M. (2004) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.2004.04184.x · Cited by 94
Schöbel, S., Neumann, S., Hertweck, M., Dislich, B., Kuhn, P., Kremmer, E., Seed, B., Baumeister, R., Haass, C., & Lichtenthaler, S. F. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m801531200 · Cited by 83
Self-citationUllrich, S., Münch, A., Neumann, S., Kremmer, E., Tatzelt, J., & Lichtenthaler, S. F. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.055608 · Cited by 70
Self-citationKim, M. L., Zhang, B., Mills, I. P., Milla, M. E., Brunden, K. R., & Lee, V. M. ‐. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.2913-08.2008 · Cited by 54
Miles, L. A., Wun, K. S., Crespi, G. A. N., Fodero‐Tavoletti, M. T., Galatis, D., Bagley, C. J., Beyreuther, K. T., Masters, C. L., Cappai, R., McKinstry, W. J., et al. (2008) · Journal of Molecular Biology · doi:10.1016/j.jmb.2007.12.036 · Cited by 52
Neumann, S., Schöbel, S., Jäger, S., Trautwein, A., Haass, C., Pietrzik, C. U., & Lichtenthaler, S. F. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m508340200 · Cited by 46
Self-citationFellgiebel, A., Kojro, E., Müller, M. J., Scheurich, A., Schmidt, L., & Fahrenholz, F. (2008) · Journal of Geriatric Psychiatry and Neurology · doi:10.1177/0891988708327810 · Cited by 34
The effects of α‐secretase ADAM10 on the proteolysis of neuregulin‐1
Freese, C., Garratt, A. N., Fahrenholz, F., & Endres, K. (2009) · FEBS Journal · doi:10.1111/j.1742-4658.2009.06889.x · Cited by 31
Expression cloning screen for modifiers of amyloid precursor protein shedding
Schöbel, S., Neumann, S., Seed, B., et al. (2006) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2005.11.003 · Cited by 28
Self-citationPasternack, J. M., Palmert, M. R., Usiak, M., Wang, R., Zürcher-Neely, H. A., Gonzalez‐DeWhitt, P. A., Fairbanks, M. B., Cheung, T. T., & Blades, D. A. (1992) · Biochemistry · doi:10.1021/bi00159a038 · Cited by 25
Cited by
Sorted by citations
The Amyloid-β Pathway in Alzheimer’s Disease
Hampel, H., Hardy, J., Blennow, K., Chen, C., Perry, G., Kim, S. H., Villemagne, V. L., Aisen, P., Vendruscolo, M., Iwatsubo, T., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01249-0 · Cited by 1,952
Alzheimer’s Disease Risk Genes and Mechanisms of Disease Pathogenesis
Karch, C. M., & Goate, A. M. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.05.006 · Cited by 1,357
“org/journ in ADAM10, the major α-secretase involved in shedding of the APP ectodomain (30), cosegregate in seven LOAD families (8,31).”
Trafficking and Proteolytic Processing of APP
Haass, C., Kaether, C., Thinakaran, G., & Sisodia, S. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006270 · Cited by 1,075
“Lowering cholesterol levels in cultured cells stimulates a-secretase cleavage of APP through mechanisms involving impaired APP endocytosis and increased steadystate levels of ADAM10 (Kojro et al. 2001).”
BackgroundInfluentialAPP processing in Alzheimer’s disease.
Zhang, Y.-W., Thompson, R., Zhang, H., & Xu, H. (2011) · Molecular Brain · doi:10.1186/1756-6606-4-3 · Cited by 983
“tion [49], implying that ADAM9 is involved only in regulated a-cleavage.”
BackgroundNot just amyloid: physiological functions of the amyloid precursor protein family
Müller, U. C., Deller, T., & Korte, M. (2017) · Nature Reviews Neuroscience · doi:10.1038/nrn.2017.29 · Cited by 634
Metadata
- Authors
- Kuhn, P., Wang, H., Dislich, B., Colombo, A., Zeitschel, U., Ellwart, J. W., Kremmer, E., Roßner, S., & Lichtenthaler, S. F.
- Affiliations
- Adolf-Butenandt-Institut für Physiologische Chemie, Physikalische Biochemie und Zellbiologie (DE)
- German Center for Neurodegenerative Diseases (DE)
- Leipzig University (DE)
- Helmholtz Munich (DE)
- Corresponding author
- Lichtenthaler, Stefan F
- ORCID
- Venue
- The EMBO Journal
- Published
- 2010-07-30
- Volume
- 29
- Issue
- 17
- Pages
- 3020-3032
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC2944055
- OpenAlex
- W2137592631
- Semantic Scholar
- dffd3996f14fbf65316cf86b6f725026d299c98e
- Cited by
- 621
- References
- 55
- Citations by year
- 2026: 19 · 2025: 17 · 2024: 27 · 2023: 32 · 2022: 37 · 2021: 42 · 2020: 41 · 2019: 46 · 2018: 47 · 2017: 42 · 2016: 42 · 2015: 42 · 2014: 44 · 2013: 44 · 2012: 49
- FWCI
- 30.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Site cant be reached (submittedVersion)
- DZNE Pub (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (SFB 596, SFB596 project B12, project Z2))
- Bundesministerium für Bildung und Forschung (SFB596)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- ADAM10, alpha-secretase, amyloid precursor protein, APP processing, amyloid-beta, beta-secretase, gamma-secretase, ADAM9, ADAM17, primary neurons, Alzheimer's disease
- MeSH terms
- ADAM10 Protein, Animals, Cell Line, Humans, Membrane Proteins, Neurons, Mass Spectrometry, Amyloid beta-Protein Precursor, Mice, ADAM Proteins, 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
