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Zinc and copper effect mechanical cell adhesion properties of the amyloid precursor protein

  • Alexander August , Sabrina Hartmann , Sandra Schilling ORCID logo , Christine Müller-Renno , Tarik Begic , Antonio J. Pierik ORCID logo , Christiane Ziegler and Stefan Kins ORCID logo EMAIL logo
Published/Copyright: October 21, 2024
Biological Chemistry
From the journal Biological Chemistry Volume 405 Issue 11-12

Abstract

The amyloid precursor protein (APP) can be modulated by the binding of copper and zinc ions. Both ions bind with low nanomolar affinities to both subdomains (E1 and E2) in the extracellular domain of APP. However, the impact of ion binding on structural and mechanical trans-dimerization properties is yet unclear. Using a bead aggregation assay (BAA), we found that zinc ions increase the dimerization of both subdomains, while copper promotes only dimerization of the E1 domain. In line with this, scanning force spectroscopy (SFS) analysis revealed an increase in APP adhesion force up to three-fold for copper and zinc. Interestingly, however, copper did not alter the separation length of APP dimers, whereas high zinc concentrations caused alterations in the structural features and a decrease of separation length. Together, our data provide clear differences in copper and zinc mediated APP trans-dimerization and indicate that zinc binding might favor a less flexible APP structure. This fact is of significant interest since changes in zinc and copper ion homeostasis are observed in Alzheimer’s disease (AD) and were reported to affect synaptic plasticity. Thus, modulation of APP trans-dimerization by copper and zinc could contribute to early synaptic instability in AD.

Keywords: Alzheimer’s disease; amyloid precursor protein; CD spectroscopy; dimerization; scanning force spectroscopy; neurodegeneration
Corresponding author: Stefan Kins, Department of Human Biology and Human Genetics, RPTU Kaiserslautern-Landau, Erwin-Schrödinger-Str. 13, D-67663 Kaiserslautern, Germany, E-mail:
Alexander August and Sabrina Hartmann contributed equally to this work.

Funding source: Landesforschungszentrum OPTIMAS

Funding source: Deutsche Forschungsgemeinschaft

Award Identifier / Grant number: KI1819/11-1 and KI1819/9-1

Funding source: Forschungsfond Rheinland-Pfalz (Biotechnology)

Acknowledgments

We thank the Landesforschungszentrum OPTIMAS (to CZ) and the Deutsche Forschungsgemeinschaft (to SK: KI1819/11-1; KI1819/9-1) for funding. TB and AJP acknowledge the Forschungsfonds Rheinland-Pfalz (Biotechnology) for the purchase of the CD spectrometer. Furthermore, we thank Luigina Hanke for excellent administrative assistance.

  1. Research ethics: Not applicable.

  2. Author contributions: The authors have accepted responsibility for the entire content of this manuscript and approved its submission. C.Z and S.K conceptualized and designed study. A.A and S.H performed the experiments. A.A, S.H., S.S, C.M, C.Z, S.K analyzed und interpretated the results. A.A, S.H, S.S, C.M wrote the manuscript. All authors reviewed the results and approved the final version of the manuscript.

  3. Use of Large Language Models, AI and Machine Learning Tools: AI was used to improve the language of individual sentences.

  4. Competing interests: The authors state no conflict of interest.

  5. Research funding: The work was supported by grants of the Landesforschungszentrum OPTIMAS and the Deutsche Forschungsgemeinschaft (KI1819/11-1; KI1819/9-1).

  6. Data availability: The raw data can be obtained on request from the corresponding author.

References

Adlard, P.A. and Bush, A.I. (2006). Metals and Alzheimer’s disease. J. Alzheimer’s Dis. JAD 10: 145–163, https://doi.org/10.3233/jad-2006-102-303.Search in Google Scholar PubMed

August, A., Schmidt, N., Klingler, J., Baumkötter, F., Lechner, M., Klement, J., Eggert, S., Vargas, C., Wild, K., Keller, S., et al.. (2019). Copper and zinc ions govern the trans-directed dimerization of APP family members in multiple ways. J. Neurochem. 151: 626–641, https://doi.org/10.1111/jnc.14716.Search in Google Scholar PubMed

Baumkötter, F., Wagner, K., Eggert, S., Wild, K., and Kins, S. (2012). Structural aspects and physiological consequences of APP/APLP trans-dimerization. Exp. Brain Res. 217: 389–395, https://doi.org/10.1007/s00221-011-2878-6.Search in Google Scholar PubMed PubMed Central

Baumkötter, F., Schmidt, N., Vargas, C., Schilling, S., Weber, R., Wagner, K., Fiedler, S., Klug, W., Radzimanowski, J., Nickolaus, S., et al.. (2014). Amyloid precursor protein dimerization and synaptogenic function depend on copper binding to the growth factor-like domain. J. Neurosci. 34: 11159–11172, https://doi.org/10.1523/jneurosci.0180-14.2014.Search in Google Scholar

Bruyère, J., Abada, Y.-S., Vitet, H., Fontaine, G., Deloulme, J.-C., Cès, A., Denarier, E., Pernet-Gallay, K., Andrieux, A., Humbert, S., et al.. (2020). Presynaptic APP levels and synaptic homeostasis are regulated by Akt phosphorylation of huntingtin. eLife 9, https://doi.org/10.7554/elife.56371.Search in Google Scholar PubMed PubMed Central

Bush, A.I. (2013). The metal theory of Alzheimer’s disease. J. Alzheimer’s Dis. 33: S277–S281, https://doi.org/10.3233/jad-2012-129011.Search in Google Scholar PubMed

Bush, A.I., Multhaup, G., Moir, R.D., Williamson, T.G., Small, D.H., Rumble, B., Pollwein, P., Beyreuther, K., and Masters, C.L. (1993). A novel zinc(II) binding site modulates the function of the beta A4 amyloid protein precursor of Alzheimer’s disease. J. Biol. Chem. 268: 16109–16112, https://doi.org/10.1016/s0021-9258(19)85394-2.Search in Google Scholar

Ciuculescu, E.-D., Mekmouche, Y., and Faller, P. (2005). Metal-binding properties of the peptide APP170-188: a model of the ZnII-binding site of amyloid precursor protein (APP). Chemistry 11: 903–909, https://doi.org/10.1002/chem.200400786.Search in Google Scholar PubMed

Craig, A.M. and Kang, Y. (2007). Neurexin-neuroligin signaling in synapse development. Curr. Opin. Neurobiol. 17: 43–52, https://doi.org/10.1016/j.conb.2007.01.011.Search in Google Scholar PubMed PubMed Central

Dahms, S.O., Hoefgen, S., Roeser, D., Schlott, B., Gührs, K.-H., and Than, M.E. (2010). Structure and biochemical analysis of the heparin-induced E1 dimer of the amyloid precursor protein. Proc. Natl Acad. Sci. USA 107: 5381–5386, https://doi.org/10.1073/pnas.0911326107.Search in Google Scholar PubMed PubMed Central

Dahms, S.O., Könnig, I., Roeser, D., Gührs, K.-H., Mayer, M.C., Kaden, D., Multhaup, G., and Than, M.E. (2012). Metal binding dictates conformation and function of the amyloid precursor protein (APP) E2 domain. J. Mol. Biol. 416: 438–452, https://doi.org/10.1016/j.jmb.2011.12.057.Search in Google Scholar PubMed

Dunsing, V., Mayer, M., Liebsch, F., Multhaup, G., and Chiantia, S. (2017). Direct evidence of amyloid precursor-like protein 1 trans interactions in cell-cell adhesion platforms investigated via fluorescence fluctuation spectroscopy. Mol. Biol. Cell 28: 3609–3620, https://doi.org/10.1091/mbc.e17-07-0459.Search in Google Scholar PubMed PubMed Central

Frederickson, C.J. (1989). Neurobiology of zinc and zinc-containing neurons. Int. Rev. Neurobiol. 31: 145–238, https://doi.org/10.1016/s0074-7742(08)60279-2.Search in Google Scholar PubMed

Gao, L., Zhao, H., Li, T., Huo, P., Chen, D., and Liu, B. (2018). Atomic force microscopy based tip-enhanced Raman spectroscopy in biology. Int. J. Mol. Sci. 19, https://doi.org/10.3390/ijms19041193.Search in Google Scholar PubMed PubMed Central

Gralle, M., Oliveira, C.L.P., Guerreiro, L.H., McKinstry, W.J., Galatis, D., Masters, C.L., Cappai, R., Parker, M.W., Ramos, C.H.I., Torriani, I., et al.. (2006). Solution conformation and heparin-induced dimerization of the full-length extracellular domain of the human amyloid precursor protein. J. Mol. Biol. 357: 493–508, https://doi.org/10.1016/j.jmb.2005.12.053.Search in Google Scholar PubMed

Hartter, D.E. and Barnea, A. (1988). Evidence for release of copper in the brain: depolarization-induced release of newly taken-up 67copper. Synapse 2: 412–415, https://doi.org/10.1002/syn.890020408.Search in Google Scholar PubMed

Hesse, L., Beher, D., Masters, C.L., and Multhaup, G. (1994). The βA4 amyloid precursor protein binding to copper. FEBS Lett. 349: 109–116, https://doi.org/10.1016/0014-5793(94)00658-x.Search in Google Scholar PubMed

Hoefgen, S., Coburger, I., Roeser, D., Schaub, Y., Dahms, S.O., and Than, M.E. (2014). Heparin induced dimerization of APP is primarily mediated by E1 and regulated by its acidic domain. J. Struct. Biol. 187: 30–37, https://doi.org/10.1016/j.jsb.2014.05.006.Search in Google Scholar PubMed

Hopt, A., Korte, S., Fink, H., Panne, U., Niessner, R., Jahn, R., Kretzschmar, H., and Herms, J. (2003). Methods for studying synaptosomal copper release. J. Neurosci. Methods 128: 159–172, https://doi.org/10.1016/s0165-0270(03)00173-0.Search in Google Scholar PubMed

Huidobro-Toro, J.P., Lorca, R.A., and Coddou, C. (2008). Trace metals in the brain: allosteric modulators of ligand-gated receptor channels, the case of ATP-gated P2X receptors. Eur. Biophys. J. 37: 301–314, https://doi.org/10.1007/s00249-007-0230-7.Search in Google Scholar PubMed

Kawahara, M., Tanaka, K.-I., and Kato-Negishi, M. (2021). Copper as a collaborative partner of zinc-induced neurotoxicity in the pathogenesis of vascular dementia. Int. J. Mol. Sci. 22, https://doi.org/10.3390/ijms22147242.Search in Google Scholar PubMed PubMed Central

Klevanski, M., Saar, M., Baumkötter, F., Weyer, S.W., Kins, S., and Müller, U.C. (2014). Differential role of APP and APLPs for neuromuscular synaptic morphology and function. Mol. Cell. Neurosci. 61: 201–210, https://doi.org/10.1016/j.mcn.2014.06.004.Search in Google Scholar PubMed

Kong, G.K.-W., Adams, J.J., Harris, H.H., Boas, J.F., Curtain, C.C., Galatis, D., Masters, C.L., Barnham, K.J., McKinstry, W.J., Cappai, R., et al.. (2007). Structural studies of the Alzheimer’s amyloid precursor protein copper-binding domain reveal how it binds copper ions. J. Mol. Biol. 367: 148–161, https://doi.org/10.1016/j.jmb.2006.12.041.Search in Google Scholar PubMed

Lambert, M., Padilla, F., and Mège, R.M. (2000). Immobilized dimers of N-cadherin-Fc chimera mimic cadherin-mediated cell contact formation: contribution of both outside-in and inside-out signals. J. Cell Sci. 113: 2207–2219, https://doi.org/10.1242/jcs.113.12.2207.Search in Google Scholar PubMed

Mayer, M.C., Kaden, D., Schauenburg, L., Hancock, M.A., Voigt, P., Roeser, D., Barucker, C., Than, M.E., Schaefer, M., and Multhaup, G. (2014). Novel zinc-binding site in the E2 domain regulates amyloid precursor-like protein 1 (APLP1) oligomerization. J. Biol. Chem. 289: 19019–19030, https://doi.org/10.1074/jbc.m114.570382.Search in Google Scholar PubMed PubMed Central

Mayer, M.C., Schauenburg, L., Thompson-Steckel, G., Dunsing, V., Kaden, D., Voigt, P., Schaefer, M., Chiantia, S., Kennedy, T.E., and Multhaup, G. (2016). Amyloid precursor-like protein 1 (APLP1) exhibits stronger zinc-dependent neuronal adhesion than amyloid precursor protein and APLP2. J. Neurochem. 137: 266–276, https://doi.org/10.1111/jnc.13540.Search in Google Scholar PubMed

Montagna, E., Dorostkar, M.M., and Herms, J. (2017). The role of APP in structural spine plasticity. Front. Mol. Neurosci. 10: 136, https://doi.org/10.3389/fnmol.2017.00136.Search in Google Scholar PubMed PubMed Central

Müller, U.C., Deller, T., and Korte, M. (2017). Not just amyloid: physiological functions of the amyloid precursor protein family. Nat. Rev. Neurosci. 18: 281–298, https://doi.org/10.1038/nrn.2017.29.Search in Google Scholar PubMed

Noda, Y., Asada, M., Kubota, M., Maesako, M., Watanabe, K., Uemura, M., Kihara, T., Shimohama, S., Takahashi, R., Kinoshita, A., et al.. (2013). Copper enhances APP dimerization and promotes Aβ production. Neurosci. Lett. 547: 10–15, https://doi.org/10.1016/j.neulet.2013.04.057.Search in Google Scholar PubMed

Paoletti, P., Vergnano, A.M., Barbour, B., and Casado, M. (2009). Zinc at glutamatergic synapses. Neuroscience 158: 126–136, https://doi.org/10.1016/j.neuroscience.2008.01.061.Search in Google Scholar PubMed

Peters, C., Muñoz, B., Sepúlveda, F.J., Urrutia, J., Quiroz, M., Luza, S., Ferrari, G.V.de, Aguayo, L.G., and Opazo, C. (2011). Biphasic effects of copper on neurotransmission in rat hippocampal neurons. J. Neurochem. 119: 78–88, https://doi.org/10.1111/j.1471-4159.2011.07417.x.Search in Google Scholar PubMed

Rae, T.D., Schmidt, P.J., Pufahl, R.A., Culotta, V.C., and O’Halloran, T.V. (1999). Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase. Science (New York, N.Y.) 284: 805–808, https://doi.org/10.1126/science.284.5415.805.Search in Google Scholar PubMed

Roberts, B.R., Ryan, T.M., Bush, A.I., Masters, C.L., and Duce, J.A. (2012). The role of metallobiology and amyloid-β peptides in Alzheimer’s disease. J. Neurochem. 120: 149–166, https://doi.org/10.1111/j.1471-4159.2011.07500.x.Search in Google Scholar PubMed

Roisman, L.C., Han, S., Chuei, M.J., Connor, A.R., and Cappai, R. (2019). The crystal structure of amyloid precursor-like protein 2 E2 domain completes the amyloid precursor protein family. FASEB J. 33: 5076–5081, https://doi.org/10.1096/fj.201802315r.Search in Google Scholar PubMed

Schikorski, T. and Stevens, C.F. (1997). Quantitative ultrastructural analysis of hippocampal excitatory synapses. J. Neurosci. 17: 5858–5867, https://doi.org/10.1523/jneurosci.17-15-05858.1997.Search in Google Scholar PubMed PubMed Central

Schilling, S., August, A., Meleux, M., Conradt, C., Tremmel, L.M., Teigler, S., Adam, V., Müller, U.C., Koo, E.H., Kins, S., et al.. (2023). APP family member dimeric complexes are formed predominantly in synaptic compartments. Cell Biosci., https://doi.org/10.1186/s13578-023-01092-6.Search in Google Scholar PubMed PubMed Central

Schilling, S., Mehr, A., Ludewig, S., Stephan, J., Zimmermann, M., August, A., Strecker, P., Korte, M., Koo, E.H., Müller, U.C., et al.. (2017). APLP1 is a synaptic cell adhesion molecule, supporting maintenance of dendritic spines and basal synaptic transmission. J. Neurosci. 37: 5345–5365, https://doi.org/10.1523/jneurosci.1875-16.2017.Search in Google Scholar

Schlief, M.L., Craig, A.M., and Gitlin, J.D. (2005). NMDA receptor activation mediates copper homeostasis in hippocampal neurons. J. Neurosci. 25: 239–246, https://doi.org/10.1523/jneurosci.3699-04.2005.Search in Google Scholar PubMed PubMed Central

Sensi, S.L., Paoletti, P., Bush, A.I., and Sekler, I. (2009). Zinc in the physiology and pathology of the CNS. Nat. Rev. Neurosci. 10: 780–791, https://doi.org/10.1038/nrn2734.Search in Google Scholar PubMed

Siddiqui, T.J. and Craig, A.M. (2011). Synaptic organizing complexes. Curr. Opin. Neurobiol. 21: 132–143, https://doi.org/10.1016/j.conb.2010.08.016.Search in Google Scholar PubMed PubMed Central

Soba, P., Eggert, S., Wagner, K., Zentgraf, H., Siehl, K., Kreger, S., Löwer, A., Langer, A., Merdes, G., Paro, R., et al.. (2005). Homo- and heterodimerization of APP family members promotes intercellular adhesion. EMBO J. 24: 3624–3634, https://doi.org/10.1038/sj.emboj.7600824.Search in Google Scholar PubMed PubMed Central

Stahl, R., Schilling, S., Soba, P., Rupp, C., Hartmann, T., Wagner, K., Merdes, G., Eggert, S., and Kins, S. (2014). Shedding of APP limits its synaptogenic activity and cell adhesion properties. Front. Cell. Neurosci. 8: 410, https://doi.org/10.3389/fncel.2014.00410.Search in Google Scholar PubMed PubMed Central

Tamano, H. and Takeda, A. (2011). Dynamic action of neurometals at the synapse. Metallomics Integr. Biometal. Sci. 3: 656–661, https://doi.org/10.1039/c1mt00008j.Search in Google Scholar PubMed

Vergnano, A.M., Rebola, N., Savtchenko, L.P., Pinheiro, P.S., Casado, M., Kieffer, B.L., Rusakov, D.A., Mulle, C., and Paoletti, P. (2014). Zinc dynamics and action at excitatory synapses. Neuron 82: 1101–1114, https://doi.org/10.1016/j.neuron.2014.04.034.Search in Google Scholar PubMed

Visser, M.J.E. and Pretorius, E. (2019). Atomic force microscopy: the characterisation of amyloid protein structure in pathology. Curr. Top. Med. Chem. 19: 2958–2973, https://doi.org/10.2174/1568026619666191121143240.Search in Google Scholar PubMed

Wang, Y. and Ha, Y. (2004). The X-ray structure of an antiparallel dimer of the human amyloid precursor protein E2 domain. Mol. Cell 15: 343–353, https://doi.org/10.1016/j.molcel.2004.06.037.Search in Google Scholar PubMed

Wang, Z., Wang, B., Yang, L., Guo, Q., Aithmitti, N., Songyang, Z., and Zheng, H. (2009). Presynaptic and postsynaptic interaction of the amyloid precursor protein promotes peripheral and central synaptogenesis. J. Neurosci. 29: 10788–10801, https://doi.org/10.1523/jneurosci.2132-09.2009.Search in Google Scholar

Wild, K., August, A., Pietrzik, C.U., and Kins, S. (2017). Structure and synaptic function of metal binding to the amyloid precursor protein and its proteolytic fragments. Front. Mol. Neurosci. 10: 21, https://doi.org/10.3389/fnmol.2017.00021.Search in Google Scholar PubMed PubMed Central

Young, T.R., Pukala, T.L., Cappai, R., Wedd, A.G., and Xiao, Z. (2018). The human amyloid precursor protein binds copper ions dominated by a picomolar-affinity site in the helix-rich E2 domain. Biochemistry 57: 4165–4176, https://doi.org/10.1021/acs.biochem.8b00572.Search in Google Scholar PubMed

Zhang, Y., Zhu, X., and Chen, B. (2022). Adhesion force evolution of protein on the surfaces with varied hydration extent: quantitative determination via atomic force microscopy. J. Colloid Interface Sci. 608: 255–264, https://doi.org/10.1016/j.jcis.2021.09.131.Search in Google Scholar PubMed

Zou, S. and Pan, B.-X. (2022). Post-synaptic specialization of the neuromuscular junction: junctional folds formation, function, and disorders. Cell Biosci. 12: 93, https://doi.org/10.1186/s13578-022-00829-z.Search in Google Scholar PubMed PubMed Central

Zuber, B., Nikonenko, I., Klauser, P., Muller, D., and Dubochet, J. (2005). The mammalian central nervous synaptic cleft contains a high density of periodically organized complexes. Proc. Natl. Acad. Sci. USA 102: 19192–19197, https://doi.org/10.1073/pnas.0509527102.Search in Google Scholar PubMed PubMed Central

Received: 2024-04-05
Accepted: 2024-10-01
Published Online: 2024-10-21
Published in Print: 2024-12-17

© 2024 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/hsz-2024-0054
Keywords for this article
Alzheimer’s disease; amyloid precursor protein; CD spectroscopy; dimerization; scanning force spectroscopy; neurodegeneration

Articles in the same Issue

  1. Frontmatter
  2. Review
  3. Structure, function, and recombinant production of EGFL7
  4. Research Articles/Short Communications
  5. Protein Structure and Function
  6. Zinc and copper effect mechanical cell adhesion properties of the amyloid precursor protein
  7. The BCL11A transcription factor stimulates the enzymatic activities of the OGG1 DNA glycosylase
  8. Cell Biology and Signaling
  9. Bioprospecting hydroxylated chalcones in in vitro model of ischemia-reoxygenation and probing NOX4 interactions via molecular docking
  10. Carnosic acid prevents heat stress-induced oxidative damage by regulating heat-shock proteins and apoptotic proteins in mouse testis
  11. Novel Techniques
  12. Simultaneous spectral illumination of microplates for high-throughput optogenetics and photobiology
  13. A platform for the early selection of non-competitive antibody-fragments from yeast surface display libraries
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