ADAM10 is the physiologically relevant, constitutive α‐secretase of the amyloid precursor protein in primary neurons

Kuhn, Peer‐Hendrik; Wang, Huanhuan; Dislich, Bastian; Colombo, Alessio; Zeitschel, Ulrike; Ellwart, Joachim W; Kremmer, Elisabeth; Roßner, Steffen; Lichtenthaler, Stefan F

doi:10.1038/emboj.2010.167

Cited by 624Alzheimer's disease research and treatmentsProtease and Inhibitor MechanismsDementia and Cognitive Impairment Research

ADAM10 is the physiologically relevant, constitutive α‐secretase of the amyloid precursor protein in primary neurons

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Kuhn, Peer‐Hendrik, Wang, Huanhuan, Dislich, Bastian, Colombo, Alessio, Zeitschel, Ulrike, Ellwart, Joachim W, Kremmer, Elisabeth, Roßner, Steffen +1 more·2010·The EMBO Journal

DOI 10.1038/emboj.2010.167PMC PMC2944055

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Abstract

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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GDE2 is required to control neuronal ADAM10 α-secretase activity.
“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]
Figure 6 reports that ADAM10 knockdown reduces α-secretase cleavage of APP in primary cortical neurons, supporting ADAM10’s neuronal α-secretase role. The paper does not address GDE2 or show that GDE2 is required to control ADAM10 activity (searched: GDE2 and its proposed regulation of ADAM10). (LLM, conf=0.85)
Experimental — accuracy not yet measured
sAPPα is neuroprotective.
“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]
ADAM10 is the major α-secretase that cleaves APP in neurons.
“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]
ADAM10 cleaves APP to generate soluble APPα (sAPPα).
“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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1 retracted

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Retracted
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“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 371 · see citing works
“…(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).”
Background
Biology and pathophysiology of the amyloid precursor protein
Zheng, H., & Koo, E. H. (2011) · Molecular Neurodegeneration · doi:10.1186/1750-1326-6-27 · Cited by 346 · see citing works
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 · see citing works
Truncated and modified amyloid-beta species
Kummer, M. P., & Heneka, M. T. (2014) · Alzheimer s Research & Therapy · doi:10.1186/alzrt258 · Cited by 338 · see citing works
“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].”
Background
Arginine 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 · see citing works
“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-citation
Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects
Vassar, R. J., 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 329 · see citing works
Self-citation
Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons
Kuhn, P., Koroniak–Szejn, K., Hogl, S., Colombo, A. V., 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 318 · see citing works
“…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-citation
Physiological Functions of APP Family ProteinsPreprint
Müller, U., & Zheng, H. (2011) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006288 · Cited by 307 · see citing works
“, 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).”
Background
Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments
Lichtenthaler, S. F., Lemberg, M. K., & Fluhrer, R. (2018) · The EMBO Journal · doi:10.15252/embj.201899456 · Cited by 298 · see citing works
“…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-citation
Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer’s disease
Zhang, Z., Song, M., Liu, X., Kang, S. S., Duong, D. M., Seyfried, N. T., Cao, X., Cheng, L., Sun, Y. E., Yu, S. P., et al. (2015) · Nature Communications · doi:10.1038/ncomms9762 · Cited by 289 · see citing works
“13). a -Secretase processing of APP occurs in the trans -Golgi network and the plasma membrane 14 .”
Background
Clearance 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 275 · see citing works
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 · see citing works
Ectodomain shedding and ADAMs in development
Weber, S., & Säftig, P. (2012) · Development · doi:10.1242/dev.076398 · Cited by 259 · see citing works
“…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;…”
Regulated intramembrane proteolysis - lessons from amyloid precursor protein processing
Lichtenthaler, S. F., Haass, C., & Steiner, H. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07248.x · Cited by 230 · see citing works
Self-citation
Amyloid precursor protein processing and bioenergetics
Wilkins, H., & Swerdlow, R. H. (2016) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2016.08.009 · Cited by 224 · see citing works
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 223 · see citing works
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., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.01.036 · Cited by 210 · see citing works
Self-citation
ADAM10 Missense Mutations Potentiate β-Amyloid Accumulation by Impairing Prodomain Chaperone Function
Suh, J., Choi, S. H., Romano, D. M., Gannon, M. A., Lesinski, A. N., Kim, D. Y., & Tanzi, R. E. (2013) · Neuron · doi:10.1016/j.neuron.2013.08.035 · Cited by 217 · see citing works
The alpha secretase ADAM10: A metalloprotease with multiple functions in the brain
Säftig, P., & Lichtenthaler, S. F. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.10.003 · Cited by 209 · see citing works
Self-citation
Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development
Robichaux, W. G., & Cheng, X. (2018) · Physiological Reviews · doi:10.1152/physrev.00025.2017 · Cited by 208 · see citing works
Alpha-secretase in Alzheimer’s disease: molecular identity, regulation and therapeutic potential
Lichtenthaler, S. F. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.07081.x · Cited by 207 · see citing works
Self-citation
Activity-Dependent Proteolytic Cleavage of Neuroligin-1
Suzuki, K., Hayashi, Y., Nakahara, S., Kumazaki, H., Prox, J., Horiuchi, K., Zeng, M., Tanimura, S., Nishiyama, Y., Osawa, S., et al. (2012) · Neuron · doi:10.1016/j.neuron.2012.10.003 · Cited by 204 · see citing works
Lipid Rafts and Alzheimer’s Disease: Protein-Lipid Interactions and Perturbation of Signaling
Hicks, D. A., Nalivaeva, N. N., & Turner, A. J. (2012) · Frontiers in Physiology · doi:10.3389/fphys.2012.00189 · Cited by 205 · see citing works
“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) .”
Background
Are amyloid‐degrading enzymes viable therapeutic targets in Alzheimer’s disease?
Nalivaeva, N., Beckett, C. S., Belyaev, N. D., & Turner, A. J. (2012) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07510.x · Cited by 178 · see citing works
Molecular mechanisms of neuropathological changes in Alzheimer’s disease: a review
Šerý, O., Povová, J., Mı́šek, I., Pešák, L., & Janout, V. (2013) · Folia Neuropathologica · doi:10.5114/fn.2013.34190 · Cited by 193 · see citing works
“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.”
Influential
Membrane Trafficking Pathways in Alzheimer 's Disease
Rajendran, L., & Annaert, W. G. (2012) · Traffic · doi:10.1111/j.1600-0854.2012.01332.x · Cited by 186 · see citing works
“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).”
Background
Exercise 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 186 · see citing works
“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.”
Background
Amyloid cascade in Alzheimer's disease: Recent advances in medicinal chemistry
Mohamed, T., Shakeri, A., & Rao, P. P. N. (2016) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2016.02.049 · Cited by 181 · see citing works
Systematic substrate identification indicates a central role for the metalloprotease ADAM10 in axon targeting and synapse function
Kuhn, P., Colombo, A. V., Schusser, B., Dreymüller, D., Wetzel, S., Schepers, U., Herber, J., Ludwig, A., Kremmer, E., Montag, D., et al. (2016) · eLife · doi:10.7554/elife.12748 · Cited by 173 · see citing works
“DOI: 10.7554/eLife.12748 1 of 29”
BackgroundMethodInfluentialSelf-citation
Structural 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 · see citing works
“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…”
Influential
Secretase inhibitors for the treatment of Alzheimer's disease: Long road ahead
Kumar, D., Ganeshpurkar, A., Kumar, D., Modi, G. P., Gupta, S., & Singh, S. K. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.02.035 · Cited by 170 · see citing works
Tipping the Scales: Peptide-Dependent Dysregulation of Neural Circuit Dynamics in Alzheimer’s Disease
Harris, S. S., Wolf, F., De Strooper, B., & Busche, M. A. (2020) · Neuron · doi:10.1016/j.neuron.2020.06.005 · Cited by 161 · see citing works
“…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,…”
Background
The Role of ADAM10 in Alzheimer’s Disease
Yuan, X., Sun, S., Tan, C., Yu, J., & Tan, L. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-170061 · Cited by 160 · see citing works
Trafficking regulation of proteins in Alzheimer’s disease
Jiang, S., Li, Y., Zhang, X., Bu, G., Xu, H., & Zhang, Y. (2014) · Molecular Neurodegeneration · doi:10.1186/1750-1326-9-6 · Cited by 160 · see citing works
“Together, this suggests that ADAM10 is the major functional α-secretase in neurons [180,181].”
Background
Nuclear 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 159 · see citing works
The Role of Zinc in Alzheimer′s Disease
Watt, N. T., Whitehouse, I. J., & Hooper, N. M. (2011) · International Journal of Alzheimer’s Disease · doi:10.4061/2011/971021 · Cited by 148 · see citing works
“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].”
Background
Synaptic dysfunction in Alzheimer's disease: the effects of amyloid beta on synaptic vesicle dynamics as a novel target for therapeutic intervention
Alifragis, P., & Marsh, J. (2018) · Neural Regeneration Research · doi:10.4103/1673-5374.230276 · Cited by 151 · see citing works
“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).”
Background
Activation of peroxisome proliferator-activated receptor α stimulates ADAM10-mediated proteolysis of APP
Corbett, G. T., Gonzalez, F. J., & Pahan, K. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1504890112 · Cited by 151 · see citing works
“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).”
Background
Endo‐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 · see citing works
Neuropeptide pituitary adenylate cyclase‐activating polypeptide (PACAP) slows down Alzheimer's disease‐like pathology in amyloid precursor protein‐transgenic mice
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 148 · see citing works
Treadmill exercise decreases amyloid-β burden possibly via activation of SIRT-1 signaling in a mouse model of Alzheimer's disease
Koo, J., Kang, E., Oh, Y.-S., Yang, D.-S., & Cho, J. (2016) · Experimental Neurology · doi:10.1016/j.expneurol.2016.11.014 · Cited by 148 · see citing works
“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 142 · see citing works
The case for low-level BACE1 inhibition for the prevention of Alzheimer disease
McDade, E., Voytyuk, I., Aisen, P. S. S., Bateman, R. J., Carrillo, M. C., Strooper, B. D., Haass, C., Reiman, E. M., Sperling, R. A., Tariot, P. N., et al. (2021) · Nature Reviews Neurology · doi:10.1038/s41582-021-00545-1 · Cited by 143 · see citing works
Self-citation
Increased 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 · see citing works
“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…”
Background
The metalloproteases meprin α and meprin β: unique enzymes in inflammation, neurodegeneration, cancer and fibrosis
Broder, C., & Becker‐Pauly, C. (2013) · Biochemical Journal · doi:10.1042/bj20121751 · Cited by 135 · see citing works
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 132 · see citing works
The substrate degradome of meprin metalloproteases reveals an unexpected proteolytic link between meprin β and ADAM10
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 · see citing works
“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].”
Background
Functions 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 133 · see citing works
“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-citation
CENP-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 · see citing works
Postnatal Disruption of the Disintegrin/Metalloproteinase ADAM10 in Brain Causes Epileptic Seizures, Learning Deficits, Altered Spine Morphology, and Defective Synaptic Functions
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 130 · see citing works
“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).”
Background
MT5-MMP is a new pro-amyloidogenic proteinase that promotes amyloid pathology and cognitive decline in a transgenic mouse model of Alzheimer’s disease
Baranger, K., Marchalant, Y., Bonnet, A. E., Crouzin, N., Carreté, A., Paumier, J., Py, N. A., Bernard, A., Bauer, C., Charrat, E., et al. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1992-1 · Cited by 127 · see citing works
“monitored by the 14D6 and 192swe antibodies, which are, respectively, considered as a readout of a- and b-secretase activities [2].”
BackgroundMethodSelf-citation
The 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 131 · see citing works
The role of membrane trafficking in the processing of amyloid precursor protein and production of amyloid peptides in Alzheimer's disease
Tan, J. Z. A., & Gleeson, P. A. (2019) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2018.11.013 · Cited by 126 · see citing works
Revisiting the Amyloid Cascade Hypothesis: From Anti-Aβ Therapeutics to Auspicious New Ways for Alzheimer’s Disease
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 127 · see citing works
“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].”
Background
Sorting 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 · see citing works
“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).”
Background
ADAM10 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 123 · see citing works
“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-citation
PERK 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 119 · see citing works
“As described in Kuhn et al (2010), lentiviruses were generated in HEK293T cells.”
MethodSelf-citation
Endocytosis 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 117 · see citing works
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 116 · see citing works
“the α-secretase ADAM10, a metalloprotease able to cleave APP within the sequence corresponding to Aβ [9,10].”
Background
In 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 · see citing works
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 116 · see citing works
Strategies to Target ADAM17 in Disease: From Its Discovery to the iRhom Revolution
Calligaris, M., Cuffaro, D., Bonelli, S., Spanò, D., Rossello, A., Nuti, E., & Scilabra, S. (2021) · Molecules · doi:10.3390/molecules26040944 · Cited by 109 · see citing works
“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].”
Background
The 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 115 · see citing works
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 115 · see citing works
“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).”
Background
Lack of a-disintegrin-and-metalloproteinase ADAM10 leads to intracellular accumulation and loss of shedding of the cellular prion protein in vivo
Altmeppen, 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 · see citing works
Metalloproteinases and their tissue inhibitors in Alzheimer’s disease and other neurodegenerative disorders
Rivera, S., García-González, L., Khrestchatisky, M., & Baranger, K. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03178-2 · Cited by 92 · see citing works
MicroRNA-144 Is Regulated by Activator Protein-1 (AP-1) and Decreases Expression of Alzheimer Disease-related A Disintegrin and Metalloprotease 10 (ADAM10)
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 111 · see citing works
The Immunoregulator Soluble TACI Is Released by ADAM10 and Reflects B Cell Activation in Autoimmunity
Hoffmann, F. S., Kuhn, P., Laurent, S. A., et al. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1402070 · Cited by 111 · see citing works
“Lentivirus production was performed as described previously (28).”
BackgroundMethodSelf-citation
Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APP swe/ PS 1dE9 mice
Mao, 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 110 · see citing works
“ADAM10 is the major a-secretase that cleaves APP to sAPPa (Kuhn et al., 2010).”
Background
Targeting ADAM10 in Cancer and Autoimmunity
Smith, T. M., Tharakan, A., & Martin, R. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00499 · Cited by 110 · see citing works
“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).”
Background
Synaptic 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 107 · see citing works
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 107 · see citing works
Metalloprotease Meprin β Generates Nontoxic N-terminal Amyloid Precursor Protein Fragments in Vivo
Jefferson, T., Čaušević, M., Keller, U. A. D., 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 105 · see citing works
5-HT4Receptors Constitutively Promote the Non-Amyloidogenic Pathway of APP Cleavage and Interact with ADAM10
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 105 · see citing works
Self-citation
APP 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 · see citing works
“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).”
Background
The 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 · see citing works
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 109 · see citing works
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 103 · see citing works
Unfolded protein response signaling by transcription factor XBP‐1 regulates ADAM10 and is affected in Alzheimer's disease
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 99 · see citing works
“tion (5), and animals with a conditional ADAM10”
Background
Vitamin 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 · see citing works
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 96 · see citing works
“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.”
Background
Nuclear 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 95 · see citing works
Trafficking and proteolytic processing of amyloid precursor protein and secretases in Alzheimer's disease development: An up-to-date review
Yuksel, M., & Tacal, Ö. (2019) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2019.172415 · Cited by 94 · see citing works
SFRPs act as negative modulators of ADAM10 to regulate retinal neurogenesis
Esteve, P., Sandonís, Á., Cardozo, M. J., et al. (2011) · Nature Neuroscience · doi:10.1038/nn.2794 · Cited by 95 · see citing works
The Membrane-Bound Aspartyl Protease BACE1: Molecular and Functional Properties in Alzheimer’s Disease and Beyond
Dislich, B., & Lichtenthaler, S. F. (2012) · Frontiers in Physiology · doi:10.3389/fphys.2012.00008 · Cited by 98 · see citing works
“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-citation
The “Memory Kinases”
Sun, M., & Alkon, D. L. (2014) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-420170-5.00002-7 · Cited by 92 · see citing works
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 · see citing works
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 · see citing works
“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).”
Background
Aβ 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 · see citing works
“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…”
Background
Regulation of Alpha-Secretase ADAM10 In vitro and In vivo: Genetic, Epigenetic, and Protein-Based Mechanisms
Endres, K., & Deller, T. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00056 · Cited by 92 · see citing works
“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

The transmembrane domain of the amyloid precursor protein is required for antiamyloidogenic processing by α-secretase ADAM10
Hitschler, L., & Lang, T. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101911 · Cited by 11 · see citing works
Putative function of ADAM9, ADAM10, and ADAM17 as APP -secretase
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P4–267: ADAM10 activation is required for green tea EGCG–induced alpha–secretase cleavage of amyloid precursor protein
Tan, J., Obregon, D. F., Rezai-Zadeh, K. P., et al. (2006) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2006.05.2006 · Cited by 4 · see citing works
α-secretase ADAM10 physically interacts with β-secretase BACE1 in neurons and regulates CHL1 proteolysis
Wang, X., Wang, C., & Pei, G. (2018) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjy001 · Cited by 17 · see citing works
Design and characterization of a novel cellular prion-derived quenched fluorimetric substrate of α-secretase
Cissé, M., Gandreuil, C., Hernandez, J., et al. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.06.065 · Cited by 22 · see citing works

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: Kuhn, Peer‐Hendrik
Wang, Huanhuan
Dislich, Bastian
Colombo, Alessio
Roßner, Steffen
Lichtenthaler, Stefan F
Venue: The EMBO Journal
Publisher: Springer Science and Business Media LLC
Published: 2010-07-30
Volume: 29
Issue: 17
Pages: 3020-3032
ISSN: 0261-4189 (ISSN-L)
1460-2075
DOI: 10.1038/emboj.2010.167
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: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
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: Health Sciences › Medicine › Physiology › 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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ADAM10 is the physiologically relevant, constitutive α‐secretase of the amyloid precursor protein in primary neurons

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