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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.
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“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]
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“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]
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“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]
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“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]
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RETRACTED ARTICLE: APP binds DR6 to trigger axon pruning and neuron death via distinct caspases
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The Amyloid-β Pathway in Alzheimer’s Disease
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“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
Targeting the β secretase BACE1 for Alzheimer's disease therapy
Yan, R., & Vassar, R. J. (2014) · The Lancet Neurology · doi:10.1016/s1474-4422(13)70276-x · Cited by 645
Inconsistencies and Controversies Surrounding the Amyloid Hypothesis of Alzheimer's Disease
Morris, G. P., Clark, I. A., & Vissel, B. (2014) · Acta Neuropathologica Communications · doi:10.1186/s40478-014-0135-5 · Cited by 522
“Furthermore lowered levels of neurotrophic sAPPα are seen in AD, and mutations which inhibit the α-secretase enzyme ADAM10, which liberates sAPPα from its precursor, are found in the promoter region and coding sequence of some individuals with AD [180].”
BackgroundSynaptic degeneration in Alzheimer disease
Tzioras, M., McGeachan, R. I., Durrant, C. S., & Spires-Jones, T. L. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-022-00749-z · Cited by 504
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“ADAM10 is the major a-secretase involved in cleavage of the APP ectodomain (Jorissen et al., 2010; Kuhn et al., 2010; Postina et al., 2004).”
BackgroundIn Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment
Guo, Q., Lehmer, C., Martínez-Sánchez, A., Rudack, T., Beck, F., Hartmann, H., Pérez‐Berlanga, M., Frottin, F., Hipp, M. S., Hartl, F. U., et al. (2018) · Cell · doi:10.1016/j.cell.2017.12.030 · Cited by 404
“1-VSVG Kuhn et al., 2010 N/A Plasmid: psPAX2 Gift from Didier Trono (unpublished data) Addgene Cat# 12260 Plasmid: pcDNA3.”
Alzheimer's DiseasePreprint
Selkoe, D. J. (2011) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a004457 · Cited by 384
“…(12 residues amino-terminal to the transmembrane domain) and is affected by one of the a-secretases, which are members of the ADAM family of membrane-anchored metalloproteases (Sisodia Cite this article as Cold Spring Harb Perspect Biol 2011;3:a004457 3 1992; Buxbaum et al. 1998; Kuhn et al. 2010).”
BackgroundBiology and pathophysiology of the amyloid precursor protein
Zheng, H., & Koo, E. H. (2011) · Molecular Neurodegeneration · doi:10.1186/1750-1326-6-27 · Cited by 377
Proteolytic processing of Alzheimer’s β‐amyloid precursor protein
Zhang, H., Ma, Q., Zhang, Y., & Xu, H. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07519.x · Cited by 344
Truncated and modified amyloid-beta species
Kummer, M. P., & Heneka, M. T. (2014) · Alzheimer s Research & Therapy · doi:10.1186/alzrt258 · Cited by 351
“Several members of the ADAM family of proteases are able to mediate this cleavage, but in neurons this function is likely to be exerted by the constitutively active ADAM10 protease [5].”
BackgroundArginine methylation next to the PY‐NLS modulates Transportin binding and nuclear import of FUS
Dormann, D., Madl, T., Valori, C. F., Bentmann, E., Tahirovic, S., Abou‐Ajram, C., Kremmer, E., Ansorge, O., Mackenzie, I. R. A., Neumann, M., et al. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.261 · Cited by 326
“HeLa cells stably expressing HA–FUS-WTor HA–FUS-P525L were generated by lentiviral transduction as described in Kuhn et al (2010), followed by selection with 0.5 m g/ml puromycin (Sigma).”
InfluentialSelf-citationVassar, R., Kuhn, P., Haass, C., Kennedy, M. E., Rajendran, L., Wong, P. C., & Lichtenthaler, S. F. (2014) · Journal of Neurochemistry · doi:10.1111/jnc.12715 · Cited by 311
Self-citationSecretome protein enrichment identifies physiological BACE1 protease substrates in neurons
Kuhn, P., Koroniak, K., Hogl, S., Colombo, A., Zeitschel, U., Willem, M., Volbracht, C., Schepers, U., Imhof, A., Hoffmeister, A., et al. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.173 · Cited by 301
“…provided by Peter Altevogt), pAb Sez6 (kindly provided by Jenny Gunnersen), PTPRF (Neuromab), mAb APP C-terminal antibody 2C11, mAb sAPP b BAWT (Kuhn et al , 2010), pAb 192wt (kindly provided by Dale Schenck), mAb 22C11 (kindly provided by Konrad Beyreuther), pAb EP2456Y clone TAU (Millipore),…”
InfluentialSelf-citationPhysiological Functions of APP Family ProteinsPreprint
Müller, U., & Zheng, H. (2011) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006288 · Cited by 339
“, HEK293 cells) a-secretase processing is the dominant pathway, primary neuronal cultures express high levels of BACE and thus generate considerable amounts of APPsb and Ab (Simons et al. 1996; Kuhn et al. 2010).”
BackgroundLichtenthaler, S. F., Lemberg, M. K., & Fluhrer, R. (2018) · The EMBO Journal · doi:10.15252/embj.201899456 · Cited by 323
“…as a -secretase for the amyloid precursor protein (APP) thereby preventing the generation of the neurotoxic amyloid-b peptide (Lammich et al , 1999; Postina et al , 2004; Jorissen et al , 2010; Kuhn et al , 2010; Suh et al , 2013), and is, thus, considered a drug target for Alzheimer’s disease.”
Self-citationZhang, Z., Song, M., Liu, X., Su Kang, S., Duong, D. M., Seyfried, N. T., Cao, X., Cheng, L., Sun, Y. E., Ping Yu, S., et al. (2015) · Nature Communications · doi:10.1038/ncomms9762 · Cited by 277
“13). a -Secretase processing of APP occurs in the trans -Golgi network and the plasma membrane 14 .”
BackgroundClearance of cerebral Aβ in Alzheimer’s disease: reassessing the role of microglia and monocytes
Zuroff, L. R., Daley, D. A., Black, K. L., & Koronyo‐Hamaoui, M. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2463-7 · Cited by 292
The role of metallobiology and amyloid-β peptides in Alzheimer's disease
Roberts, B. R., Ryan, T. M., Bush, A. I., Masters, C. L., & Duce, J. A. (2012) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07500.x · Cited by 266
Ectodomain shedding and ADAMs in development
Weber, S., & Säftig, P. (2012) · Development · doi:10.1242/dev.076398 · Cited by 259
“…et al., 2007; Li et al., 2007; Schulte et al., 2007; Schulz et al., 2008; Waldhauer et al., 2008; Bloch et al., 2009; Jorissen et al., 2010; Kuhn et al., 2010; Altmeppen et al., 2011) ADAM12 collagen IV, delta-like ligand 1, HB-EGF, fibronectin, gelantin, IGFBP-3/-5 (Loechel et al., 2000;…”
Lichtenthaler, S. F., Haass, C., & Steiner, H. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07248.x · Cited by 205
Self-citationAmyloid precursor protein processing and bioenergetics
Wilkins, H., & Swerdlow, R. H. (2016) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2016.08.009 · Cited by 228
AMP‐activated protein kinase: a potential player in Alzheimer’s disease
Salminen, A., Kaarniranta, K., Haapasalo, A., Soininen, H. S., & Hiltunen, M. O. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07331.x · Cited by 224
The E3 Ligase Parkin Maintains Mitochondrial Integrity by Increasing Linear Ubiquitination of NEMO
Müller-Rischart, A. K., Pilsl, A., Beaudette, P., Patra, M., Hadian, K., Funke, M., Peis, R., Deinlein, A., Schweimer, C., Kuhn, P.-H., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.01.036 · Cited by 208
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Self-citationIntracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development
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Alpha-secretase in Alzheimer’s disease: molecular identity, regulation and therapeutic potential
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Self-citationActivity-Dependent Proteolytic Cleavage of Neuroligin-1
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Lipid Rafts and Alzheimer’s Disease: Protein-Lipid Interactions and Perturbation of Signaling
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“Recent investigations have suggested that ADAM10 is the principal APP secretase in primary neurons, with ADAM17 playing more of an auxiliary role (Kuhn et al., 2010; Lichtenthaler, 2010) .”
BackgroundAre amyloid-degrading enzymes viable therapeutic targets in Alzheimer’s disease?
Nalivaeva, N. N., Beckett, C., Belyaev, N. D., & Turner, A. J. (2012) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07510.x · Cited by 169
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Šerý, O., Povová, J., Mı́šek, I., Pešák, L., & Janout, V. (2013) · Folia Neuropathologica · doi:10.5114/fn.2013.34190 · Cited by 198
“Kuhn PH, Wang H, Dislich B, Colombo A, Zeitschel U, Ellwart JW, Kremmer E, Rossner S, Lichtenthaler SF. ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons.”
InfluentialMembrane Trafficking Pathways in Alzheimer's Disease
Rajendran, L., & Annaert, W. (2012) · Traffic · doi:10.1111/j.1600-0854.2012.01332.x · Cited by 171
“α-Secretase/ADAM Thus far, three related metalloproteases of the ADAM (a disintegrin and metalloproteases) family, ADAM-9, ADAM10 and ADAM-17 (or Tumor necrosis factor-α-converting enzyme (TACE)), have been implicated as potential αsecretases, of which ADAM-10 is the main secretase (23).”
BackgroundExercise and BDNF reduce Aβ production by enhancing α‐secretase processing of APP
Nigam, S. M., Xu, S., Kritikou, J. S., Marosi, K., Brodin, L., & Mattson, M. P. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.14034 · Cited by 193
“ADAM10, the main active component of asecretase (Kuhn et al. 2010), was assessed in RA-differentiated SHSY5Y cells treated with batimastat, BDNF, batimastat plus BDNF, or vehicle control.”
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Mohamed, T., Shakeri, A., & Rao, P. P. N. (2016) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2016.02.049 · Cited by 185
Kuhn, P.-H., Colombo, A. V., Schusser, B., Dreymueller, D., Wetzel, S., Schepers, U., Herber, J., Ludwig, A., Kremmer, E., Montag, D., et al. (2016) · eLife · doi:10.7554/elife.12748 · Cited by 163
“DOI: 10.7554/eLife.12748 1 of 29”
BackgroundMethodInfluentialSelf-citationStructural Basis for Regulated Proteolysis by the α-Secretase ADAM10
Seegar, T. C. M., Killingsworth, L. B., Saha, N., Meyer, P. A., Patra, D., Zimmerman, B., Janes, P. W., Rubinstein, E., Nikolov, D. B., Skiniotis, G., et al. (2017) · Cell · doi:10.1016/j.cell.2017.11.014 · Cited by 170
“The human genome encodes 22 different ADAMs, essential for numerous developmental events (Weber and Saftig, 2012) including spermatogenesis, fertilization (Cho et al., 1998), immune and gastrointestinal system development (Jones et al., 2016), angiogenesis (Glomski et al., 2011), and development of the CNS (Jorissen e…”
InfluentialSecretase inhibitors for the treatment of Alzheimer's disease: Long road ahead
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“…pathway, APP may be competitively cleaved by a-secretase (mainly disintegrin and metalloproteinase domain-containing protein 10 [ADAM10]) (Kuhn et al., 2010) or h-secretase (matrix metalloproteinases such as MT5-MMP) (Willem et al., 2015), liberating two additional soluble fragments,…”
BackgroundThe Role of ADAM10 in Alzheimer’s Disease
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“Together, this suggests that ADAM10 is the major functional α-secretase in neurons [180,181].”
BackgroundNuclear egress of TDP-43 and FUS occurs independently of Exportin-1/CRM1
Ederle, H., Funk, C., Abou‐Ajram, C., Hutten, S., Funk, E. B. E., Kehlenbach, R. H., Bailer, S. M., & Dormann, D. (2018) · Scientific Reports · doi:10.1038/s41598-018-25007-5 · Cited by 170
The Role of Zinc in Alzheimer′s Disease
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“Although fibroblasts from ADAM10−/− mice showed no deficiency in α-secretase activity, probably due to compensation by ADAM17 [60], a recent detailed study has provided strong evidence that ADAM10 is the physiologically relevant constitutive α-secretase in primary neurons [61].”
BackgroundAlifragis, P., & Marsh, J. (2018) · Neural Regeneration Research · doi:10.4103/1673-5374.230276 · Cited by 156
“Several members of the ADAM family of metalloproteases have been reported to possess α-secretase activity with ADAM10 being the major α-secretase that cleaves APP in the brain (Lammich et al., 1999; Kuhn et al., 2010; Prox et al., 2013).”
BackgroundCorbett, G. T., Gonzalez, F. J., & Pahan, K. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1504890112 · Cited by 151
“Of note, ADAM9 and ADAM17 do not recover α-secretase proteolysis of APP in the absence of ADAM10 (5), neuron-specific overexpression of ADAM10 decreases Aβ load in a mouse model of AD (6), and impaired ADAM10 trafficking to the synapse generates a model of sporadic AD (7).”
BackgroundEndo‐lysosomal and autophagic dysfunction: a driving factor in Alzheimer's disease?
Whyte, L. S., Lau, A. A., Hemsley, K. M., Hopwood, J. J., & Sargeant, T. J. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.13935 · Cited by 150
Rat, D., Schmitt, U., Tippmann, F., Dewachter, I., Theunis, C., Wieczerzak, E., Postina, R., LEUVEN, F. V., Fahrenholz, F., & Kojro, E. (2011) · The FASEB Journal · doi:10.1096/fj.10-180133 · Cited by 155
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“Inhibition of Aβ production, in the nonamyloidogenic pathway, results from the cleavage of APP by a disintegrin and metalloproteinase domain-containing protein 10 (ADAM-10) and γ secretase (Kuhn et al., 2010).”
Therapeutic Strategies Targeting Amyloid-β in Alzheimer’s Disease
Pinheiro, L. M. V., & Faustino, C. M. C. (2019) · Current Alzheimer Research · doi:10.2174/1567205016666190321163438 · Cited by 144
The case for low-level BACE1 inhibition for the prevention of Alzheimer disease
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Self-citationIncreased CSF APPs-α levels in patients with Alzheimer disease treated with acitretin
Endres, K., Fahrenholz, F., Lotz, J., Hiemke, C., Teipel, S. J., Lieb, K., Tüscher, O., & Fellgiebel, A. (2014) · Neurology · doi:10.1212/wnl.0000000000001017 · Cited by 138
“Such a competing outcome for the enzymes’ activities has been repeatedly demonstrated in cell culture experiments and in animal studies: for murine primary neurons, for example, it has been found that knockdown of ADAM10 resulted in a mild upregulation of b-secretase activity.(1) However, there are conflicting data th…”
BackgroundBroder, C., & Becker‐Pauly, C. (2013) · Biochemical Journal · doi:10.1042/bj20121751 · Cited by 135
N -glycan and Alzheimer's disease
Kizuka, Y., Kitazume, S., & Taniguchi, N. (2017) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2017.04.012 · Cited by 133
Jefferson, T., Keller, U. A. D., Bellac, C. L., Metz, V. V., Broder, C., Hedrich, J., Ohler, A., Maier, W., Magdolen, V., Sterchi, E. E., et al. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-1106-2 · Cited by 133
“As the constitutive a-secretase of amyloid protein [31, 32], ADAM10 is presumed to prevent the formation of aggregates of neurodegenerative amyloid b peptides derived from the amyloid precursor molecule by cleavage by b- and c-secretases [33].”
BackgroundFunctions of ‘A disintegrin and metalloproteases (ADAMs)’ in the mammalian nervous system
Hsia, H., Tüshaus, J., Brummer, T., Zheng, Y., Scilabra, S. D., & Lichtenthaler, S. F. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03173-7 · Cited by 148
“Similarly to ADAM10, which acts as the neuronal α-secretase under non-stimulated, constitutive conditions [91, 92, 138], ADAM17-mediated cleavage of APP releases its soluble ectodomain (sAPPα), thereby initiating the neuroprotective non-amyloidogenic pathway of APP processing and potentially reducing generation of the…”
BackgroundSelf-citationCENP-C facilitates the recruitment of M18BP1 to centromeric chromatin
Dambacher, S., Deng, W., Hahn, M., Sadic, D., Fröhlich, J., Nuber, A., Hoischen, C., Diekmann, S., Leonhardt, H., & Schotta, G. (2012) · Nucleus · doi:10.4161/nucl.18955 · Cited by 131
Prox, J., Bernreuther, C., Altmeppen, H. C., Grendel, J., Glatzel, M., D’Hooge, R., Stroobants, S., Ahmed, T., Balschun, D., Willem, M., et al. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.5910-12.2013 · Cited by 139
“This not only supports our chosen strategy but also underscores that in adult neurons ADAM10 is the most essential protease for the ectodomain shedding of APP (Jorissen et al., 2010; Kuhn et al., 2010).”
BackgroundBaranger, K., Marchalant, Y., Bonnet, A. E., Crouzin, N., Carrete, A., Paumier, J.-M., Py, N. A., Bernard, A., Bauer, C., Charrat, E., et al. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1992-1 · Cited by 133
“monitored by the 14D6 and 192swe antibodies, which are, respectively, considered as a readout of a- and b-secretase activities [2].”
BackgroundMethodSelf-citationThe Role and Therapeutic Targeting of α-, β- and γ-Secretase in Alzheimer's Disease
MacLeod, R., Hillert, E., Cameron, R. T., & Baillie, G. S. (2015) · Future Science OA · doi:10.4155/fso.15.9 · Cited by 136
Tan, J. Z. A., & Gleeson, P. A. (2019) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2018.11.013 · Cited by 137
Uddin, M. S., Kabir, M. T., Rahman, M. S., Behl, T., Jeandet, P., Ashraf, G. M., Najda, A., Bin-Jumah, M. N., El-Seedi, H. R., & Abdel‐Daim, M. M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21165858 · Cited by 131
“Since α-secretase processing of APP includes cleavage within the Aβ peptide sequence, preventing the formation of Aβ, activation of APP α-secretase cleavage is regarded as an effective AD treatment [109].”
BackgroundSorting receptor SORLA – a trafficking path to avoid Alzheimer disease
Willnow, T. E., & Andersen, O. M. (2013) · Journal of Cell Science · doi:10.1242/jcs.125393 · Cited by 121
“Several members of the disintegrin and metalloprotease (ADAM) family, particularly ADAM10, are candidate a-secretases (Kuhn et al., 2010). c-secretase is a multimeric complex of presenilin, nicastrin, anterior pharynx defective-1 (APH1), and presenilin enhancer-2 (Pen-2, also known as PSENEN).”
BackgroundADAM10 and ADAM17 promote SARS‐CoV‐2 cell entry and spike protein‐mediated lung cell fusion
Jocher, G., Grass, V., Tschirner, S. K., Riepler, L., Breimann, S., Kaya, T., Oelsner, M., Hamad, M. S., Hofmann, L. I., Blobel, C., et al. (2022) · EMBO Reports · doi:10.15252/embr.202154305 · Cited by 134
“Both proteases are also linked to pathophysiological conditions, such as Alzheimer’s disease (ADAM10) and inflammation (ADAM17; Peschon et al , 1998; Lammich et al , 1999; Jorissen et al , 2010; Kuhn et al , 2010).”
Self-citationPERK activation mitigates tau pathology in vitro and in vivo
Bruch, J., Xu, H. W., Rösler, T. W., Andrade, A. D., Kuhn, P., Lichtenthaler, S. F., Arzberger, T., Winklhofer, K. F., Müller, U., & Höglinger, G. U. (2017) · EMBO Molecular Medicine · doi:10.15252/emmm.201606664 · Cited by 128
“As described in Kuhn et al (2010), lentiviruses were generated in HEK293T cells.”
MethodSelf-citationEndocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer’s disease
Marcello, E. E., Saraceno, C., Musardo, S., Vara, H., de la Fuente, A. G., Pelucchi, S., Marino, D. D., Borroni, B., Tramontano, A. L., Pérez‐Otaño, I., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci65401 · Cited by 120
Dendritic Spines in Alzheimer’s Disease: How the Actin Cytoskeleton Contributes to Synaptic Failure
Pelucchi, S., Stringhi, R., & Marcello, E. E. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21030908 · Cited by 117
“the α-secretase ADAM10, a metalloprotease able to cleave APP within the sequence corresponding to Aβ [9,10].”
BackgroundIn situ architecture of neuronal α-Synuclein inclusions
Trinkaus, V. A., Riera-Tur, I., Martínez-Sánchez, A., Bäuerlein, F. J. B., Guo, Q., Arzberger, T., Baumeister, W. P., Dudanova, I., Hipp, M. S., Hartl, F. U., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22108-0 · Cited by 118
Cleavage of Neuregulin-1 by BACE1 or ADAM10 Protein Produces Differential Effects on Myelination
Luo, X., Prior, M., He, W., Hu, X., Tang, X., Shen, W.-Z., Yadav, S. P., Kiryu‐Seo, S., Miller, R. H., Trapp, B. D., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.251538 · Cited by 121
Strategies to Target ADAM17 in Disease: From Its Discovery to the iRhom Revolution
Calligaris, M., Cuffaro, D., Bonelli, S., Spanò, D. P., Rossello, A., Nuti, E., & Scilabra, S. D. (2021) · Molecules · doi:10.3390/molecules26040944 · Cited by 123
“While ADAM10 has been reported to be the physiological “constitutive alpha-secretase” of APP, ADAM17 is known to be the “stimulated alpha-secretase” [143,144].”
BackgroundThe ADAMs family of proteases as targets for the treatment of cancer
Mullooly, M., McGowan, P. M., Crown, J. P., & Duffy, M. J. (2016) · Cancer Biology & Therapy · doi:10.1080/15384047.2016.1177684 · Cited by 120
Therapeutic Potential of Secreted Amyloid Precursor Protein APPsα
Mockett, B. G., Richter, M., Abraham, W. C., & Müller, U. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00030 · Cited by 127
“In neurons ADAM10 serves as the major physiological α-secretase as demonstrated by pharmacological inhibition and knockdown in vitro, as well as brain-specific knockout (KO) in vivo (Kuhn et al., 2010; Colombo et al., 2013; Prox et al., 2013).”
BackgroundAltmeppen, H. C., Prox, J., Puig, B., Kluth, M. A., Bernreuther, C., Thurm, D., Jorissen, E., Petrowitz, B., Bartsch, U., Strooper, B. D., et al. (2011) · Molecular Neurodegeneration · doi:10.1186/1750-1326-6-36 · Cited by 112
Rivera, S., García-González, L., Khrestchatisky, M., & Baranger, K. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03178-2 · Cited by 111
Cheng, C., Li, W., Zhang, Z., Yoshimura, S., Hao, Q., Zhang, C., & Wang, Z. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.381392 · Cited by 115
Hoffmann, F. S., Kuhn, P., Laurent, S. A., Hauck, S. M., Berer, K., Wendlinger, S. A., Krumbholz, M., Khademi, M., Olsson, T. P., Dreyling, M. H., et al. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1402070 · Cited by 112
“Lentivirus production was performed as described previously (28).”
BackgroundMethodSelf-citationMao, Y., Guo, Z., Zheng, T., Jiang, Y., Yan, Y., Yin, X., Chen, Y., & Zhang, B. (2016) · Aging Cell · doi:10.1111/acel.12498 · Cited by 113
“ADAM10 is the major a-secretase that cleaves APP to sAPPa (Kuhn et al., 2010).”
BackgroundTargeting ADAM10 in Cancer and Autoimmunity
Smith, T. M., Tharakan, A., & Martin, R. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00499 · Cited by 116
“Despite this, the use of ADAM10 inhibitors as a clinical intervention should be carefully evaluated due to ADAM10’s role in the cleavage of amyloid plaque precursors (58, 59).”
BackgroundSynaptic Dysfunction in Alzheimer’s Disease
Marcello, E. E., Epis, R., Saraceno, C., & Luca, M. D. (2012) · Advances in experimental medicine and biology · doi:10.1007/978-3-7091-0932-8_25 · Cited by 115
Central Angiotensin II Stimulation Promotes β Amyloid Production in Sprague Dawley Rats
Zhu, D., Shi, J., Zhang, Y., Wang, B., Liu, W., Chen, Z., & Tong, Q. (2011) · PLoS ONE · doi:10.1371/journal.pone.0016037 · Cited by 112
Metalloprotease Meprin β Generates Nontoxic N-terminal Amyloid Precursor Protein Fragments in Vivo
Jefferson, T., Čaušević, M., auf dem Keller, U., Schilling, O., Isbert, S., Geyer, R., Maier, W., Tschickardt, S., Jumpertz, T., Weggen, S., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.252718 · Cited by 108
Cochet, M., Donneger, R., Cassier, E., Gaven, F., Lichtenthaler, S. F., Marin, P., Bockaert, J., Dumuis, A., & Claeysen, S. (2012) · ACS Chemical Neuroscience · doi:10.1021/cn300095t · Cited by 111
Self-citationAPP Function and Lipids: A Bidirectional Link
Grimm, M. O. W., Mett, J., Grimm, H. S., & Hartmann, T. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00063 · Cited by 104
“Members of the ADAM (a disintegrin and metalloprotease) protein family have been identified as catalytically active α-secretases with ADAM10 representing the physiologically relevant, constitutive α-secretase in neurons (Lammich et al., 1999; Kuhn et al., 2010).”
BackgroundThe Neuroprotective Properties of the Amyloid Precursor Protein Following Traumatic Brain Injury
Plummer, S. L., van den Heuvel, C., Thornton, E., Corrigan, F., & Cappai, R. (2016) · Aging and Disease · doi:10.14336/ad.2015.0907 · Cited by 103
Mechanistic Link between Vitamin B12 and Alzheimer’s Disease
Lauer, A. A., Grimm, H. S., Apel, B., Golobrodska, N., Kruse, L., Ratanski, E., Schulten, N., Schwarze, L., Slawik, T., Sperlich, S., et al. (2022) · Biomolecules · doi:10.3390/biom12010129 · Cited by 121
The Role of Adams in Notch Signaling
Groot, A. J., & Vooijs, M. (2012) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-0899-4_2 · Cited by 110
Reinhardt, S., Schuck, F., Grösgen, S., Riemenschneider, M. J., Hartmann, T., Postina, R., Grimm, M. O. W., & Endres, K. (2013) · The FASEB Journal · doi:10.1096/fj.13-234864 · Cited by 107
“tion (5), and animals with a conditional ADAM10”
BackgroundVitamin D and Its Analogues Decrease Amyloid-β (Aβ) Formation and Increase Aβ-Degradation
Grimm, M. O. W., Thiel, A., Lauer, A. A., Winkler, J., Lehmann, J., Regner-Nelke, L., Nelke, C., Janitschke, D., Benoist, C., Streidenberger, O., et al. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18122764 · Cited by 97
Biomarker-based dissection of neurodegenerative diseases
Olsson, B., Zetterberg, H., Hampel, H. J., & Blennow, K. (2011) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2011.04.006 · Cited by 102
“Several proteases with a-secretase activity has been described but recent data suggest that ADAM10 is the main player (Kuhn et al., 2010; Lammich et al., 1999) and transgenic overexpression of ADAM10 reduces the amount of Ab plaque formation in APP transgenic mice (Postina et al.”
BackgroundNuclear signalling by membrane protein intracellular domains: The AICD enigma
Beckett, C., Nalivaeva, N. N., Belyaev, N. D., & Turner, A. J. (2011) · Cellular Signalling · doi:10.1016/j.cellsig.2011.10.007 · Cited by 101
Yuksel, M., & Tacal, Ö. (2019) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2019.172415 · Cited by 99
SFRPs act as negative modulators of ADAM10 to regulate retinal neurogenesis
Esteve, P., Sandonís, Á., Cardozo, M. J., Malapeira, J., Ibáñez, C., Crespo, I., Marcos, S., González-García, S., Toribio, M. L., Arribas, J., et al. (2011) · Nature Neuroscience · doi:10.1038/nn.2794 · Cited by 94
Dislich, B., & Lichtenthaler, S. F. (2012) · Frontiers in Physiology · doi:10.3389/fphys.2012.00008 · Cited by 102
“ADAM10, a member of the ADAM (a disintegrin and metalloprotease) family of proteases, has α-secretase activity in vitro and in vivo and has been identified as the constitutively cleaving α-secretase in neurons (Lammich et al., 1999; Postina et al., 2004; Jorissen et al., 2010; Kuhn et al., 2010).”
Self-citationSun, M., & Alkon, D. L. (2014) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-420170-5.00002-7 · Cited by 94
Proteolytic processing of the prion protein in health and disease.
Altmeppen, H. C., Puig, B., Dohler, F., Thurm, D., Falker‐Gieske, C., Krasemann, S., & Glatzel, M. (2012) · Europe PMC (PubMed Central) · Cited by 93
Axonal transport of APP and the spatial regulation of APP cleavage and function in neuronal cells
Brunholz, S., Sisodia, S., Lorenzo, A., Deyts, C., Kins, S., & Morfini, G. (2012) · Experimental Brain Research · doi:10.1007/s00221-011-2870-1 · Cited by 92
“From several known zinc-dependent proteases, ADAM10 (a disintegrin and metalloprotease) represents the main secretase responsible for cleavage of APP at the a-cleavage site in neurons (Kuhn et al. 2010).”
BackgroundAβ leads to Ca2+ signaling alterations and transcriptional changes in glial cells
Grolla, A. A., Fakhfouri, G., Balzaretti, G., Marcello, E. E., Gardoni, F., Canonico, P. L., Luca, M. D., Genazzani, A. A., & Lim, D. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.05.005 · Cited by 93
“Alternatively and antagonistically, APP can be subject to proteolytic cleavage by -secretase, specifically shown to be a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) (Endres and Fahrenholz, 2010; Jorissen et al., 2010; Kuhn et al., 2010), which occurs within the sequence of A , thus precludi…”
BackgroundEndres, K., & Deller, T. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00056 · Cited by 99
“ADAM10 cleaves APP at the alpha-secretase cleavage site and in vitro as well as in vivo studies have implicated ADAM10 as the biologically most relevant neuronal alpha-secretase (e.g., Postina et al., 2004; Jorissen et al., 2010; Kuhn et al., 2010).”
BackgroundInfluential
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
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