Effects of δ-Catenin on APP by Its Interaction with Presenilin-1

  • Dai, Weiye (College of Pharmacy and Research Institute for Drug Development, Chonnam National University) ;
  • Ryu, Taeyong (College of Pharmacy and Research Institute for Drug Development, Chonnam National University) ;
  • Kim, Hangun (College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University) ;
  • Jin, Yun Hye (College of Pharmacy and Research Institute for Drug Development, Chonnam National University) ;
  • Cho, Young-Chang (College of Pharmacy and Research Institute for Drug Development, Chonnam National University) ;
  • Kim, Kwonseop (College of Pharmacy and Research Institute for Drug Development, Chonnam National University)
  • Received : 2018.06.25
  • Accepted : 2018.10.18
  • Published : 2019.01.31


Alzheimer's disease (AD) is the most frequent age-related human neurological disorder. The characteristics of AD include senile plaques, neurofibrillary tangles, and loss of synapses and neurons in the brain. ${\beta}-Amyloid$ ($A{\beta}$) peptide is the predominant proteinaceous component of senile plaques. The amyloid hypothesis states that $A{\beta}$ initiates the cascade of events that result in AD. Amyloid precursor protein (APP) processing plays an important role in $A{\beta}$ production, which initiates synaptic and neuronal damage. ${\delta}-Catenin$ is known to be bound to presenilin-1 (PS-1), which is the main component of the ${\gamma}-secretase$ complex that regulates APP cleavage. Because PS-1 interacts with both APP and ${\delta}-catenin$, it is worth studying their interactive mechanism and/or effects on each other. Our immunoprecipitation data showed that there was no physical association between ${\delta}-catenin$ and APP. However, we observed that ${\delta}-catenin$ could reduce the binding between PS-1 and APP, thus decreasing the PS-1 mediated APP processing activity. Furthermore, ${\delta}-catenin$ reduced PS-1-mediated stabilization of APP. The results suggest that ${\delta}-catenin$ can influence the APP processing and its level by interacting with PS-1, which may eventually play a protective role in the degeneration of an Alzheimer's disease patient.

E1BJB7_2019_v42n1_36_f0001.png 이미지

Fig. 1. The interaction between APP, δ-catenin, and PS-1.

E1BJB7_2019_v42n1_36_f0002.png 이미지

Fig. 2. The binding between APP and PS1 is reduced by δ-catenin in a dose-dependent manner.

E1BJB7_2019_v42n1_36_f0003.png 이미지

Fig. 3. δ-Catenin-mediated alteration of APP protein levels and processing.

E1BJB7_2019_v42n1_36_f0004.png 이미지

Fig. 4. δ-Catenin overexpression-mediated alteration of C99 expression.

E1BJB7_2019_v42n1_36_f0005.png 이미지

Fig. 5. δ-Catenin-related reduction of PS1-mediated stabilization on APP (C99).

E1BJB7_2019_v42n1_36_f0006.png 이미지

Fig. 6. δ-Catenin-mediated decrease of APP (C99) protein stability.

E1BJB7_2019_v42n1_36_f0007.png 이미지

Fig. 7. A proposed model illustrates how δ-catenin regulates APP processing.


Supported by : National Research Foundation of Korea (NRF)


  1. Arikkath, J., Peng, I.F., Ng, Y.G., Israely, I., Liu, X., Ullian, E.M., and Reichardt, L.F. (2009). Delta-catenin regulates spine and synapse morphogenesis and function in hippocampal neurons during development. J. Neurosci. 29, 5435-5442.
  2. Berger-Sweeney, J., McPhie, D.L., Arters, J.A., Greenan, J., Oster-Granite, M.L., and Neve, R.L. (1999). Impairments in learning and memory accompanied by neurodegeneration in mice transgenic for the carboxyl-terminus of the amyloid precursor protein. Brain Res. Mol. Brain Res. 66, 150-162.
  3. Blennow, K., de Leon, M.J., and Zetterberg, H. (2006). Alzheimer's disease. Lancet. 368, 387-403.
  4. Bredesen, D.E. (2009). Neurodegeneration in Alzheimer's disease: caspases and synaptic element interdependence. Mol. Neurodegener. 4, 27.
  5. Cho, K., Lee, M., Gu, D., Munoz, W.A., Ji, H., Kloc, M., and McCrea, P.D. (2011). Kazrin, and its binding partners ARVCF- and deltacatenin, are required for Xenopus laevis craniofacial development. Dev. Dyn. 240, 2601-2612.
  6. Czech, C., Lesort, M., Tremp, G., Terro, F., Blanchard, V., Schombert, B., Carpentier, N., Dreisler, S., Bonici, B., Takashima, A., et al. (1998). Characterization of human presenilin 1 transgenic rats: increased sensitivity to apoptosis in primary neuronal cultures. Neuroscience 87, 325-336.
  7. Deguchi, M., Iizuka, T., Hata, Y., Nishimura, W., Hirao, K., Yao, I., Kawabe, H., and Takai, Y. (2000). PAPIN. A novel multiple PSD-95/Dlg-A/ZO-1 protein interacting with neural plakophilin-related armadillo repeat protein/delta-catenin and p0071. J. Biol. Chem. 275, 29875-29880.
  8. Doan, A., Thinakaran, G., Borchelt, D.R., Slunt, H.H., Ratovitsky, T., Podlisny, M., Selkoe, D.J., Seeger, M., Gandy, S.E., Price, D.L., et al. (1996). Protein topology of presenilin 1. Neuron 17, 1023-1030.
  9. Fujita, T., Okada, T., Hayashi, S., Jahangeer, S., Miwa, N., and Nakamura, S. (2004). Delta-catenin/NPRAP (neural plakophilinrelated armadillo repeat protein) interacts with and activates sphingosine kinase 1. Biochem. J. 382, 717-723.
  10. Gao, Y., and Pimplikar, S.W. (2001). The gamma -secretase-cleaved C-terminal fragment of amyloid precursor protein mediates signaling to the nucleus. Proc. Natl. Acad. Sci. USA 98, 14979-14984.
  11. Gu, D., Tonthat, N.K., Lee, M., Ji, H., Bhat, K.P., Hollingsworth, F., Aldape, K.D., Schumacher, M.A., Zwaka, T.P., and McCrea, P.D. (2011). Caspase-3 cleavage links delta-catenin to the novel nuclear protein ZIFCAT. J. Biol. Chem. 286, 23178-23188.
  12. Ide, N., Hata, Y., Deguchi, M., Hirao, K., Yao, I., and Takai, Y. (1999). Interaction of S-SCAM with neural plakophilin-related Armadillorepeat protein/delta-catenin. Biochem. Biophys. Res. Commun. 256, 456-461.
  13. Izawa, I., Nishizawa, M., Ohtakara, K., and Inagaki, M. (2002). Densin-180 interacts with delta-catenin/neural plakophilin-related armadillo repeat protein at synapses. J. Biol. Chem. 277, 5345-5350.
  14. Jeong, S. (2017). Molecular and cellular basis of neurodegeneration in Alzheimer's disease. Mol. Cells 40, 613-620.
  15. Jun, G., Moncaster, J.A., Koutras, C., Seshadri, S., Buros, J., McKee, A.C., Levesque, G., Wolf, P.A., St George-Hyslop, P., Goldstein, L.E., et al. (2012). delta-Catenin is genetically and biologically associated with cortical cataract and future Alzheimer-related structural and functional brain changes. PLoS ONE 7, e43728.
  16. Kim, H., Han, J.R., Park, J., Oh, M., James, S.E., Chang, S., Lu, Q., Lee, K.Y., Ki, H., Song, W.J., et al. (2008). Delta-catenin-induced dendritic morphogenesis. An essential role of p190RhoGEF interaction through Akt1-mediated phosphorylation. J. Biol. Chem. 283, 977-987.
  17. Kim, K., Sirota, A., Chen Yh, Y.H., Jones, S.B., Dudek, R., Lanford, G.W., Thakore, C., and Lu, Q. (2002). Dendrite-like process formation and cytoskeletal remodeling regulated by delta-catenin expression. Exp. Cell Res. 275, 171-184.
  18. Kosik, K.S., Donahue, C.P., Israely, I., Liu, X., and Ochiishi, T. (2005). Delta-catenin at the synaptic-adherens junction. Trends Cell Biol. 15, 172-178.
  19. Koutras, C., and Levesque, G. (2011). Identification of novel NPRAP/delta-catenin-interacting proteins and the direct association of NPRAP with dynamin 2. PLoS ONE 6, e25379.
  20. Laura, R.P., Witt, A.S., Held, H.A., Gerstner, R., Deshayes, K., Koehler, M.F., Kosik, K.S., Sidhu, S.S., and Lasky, L.A. (2002). The Erbin PDZ domain binds with high affinity and specificity to the carboxyl termini of delta-catenin and ARVCF. J. Biol. Chem. 277, 12906-12914.
  21. Lu, D.C., Soriano, S., Bredesen, D.E., and Koo, E.H. (2003). Caspase cleavage of the amyloid precursor protein modulates amyloid betaprotein toxicity. J. Neurochem. 87, 733-741.
  22. Lu, Q., Mukhopadhyay, N.K., Griffin, J.D., Paredes, M., Medina, M., and Kosik, K.S. (2002). Brain armadillo protein delta-catenin interacts with Abl tyrosine kinase and modulates cellular morphogenesis in response to growth factors. J. Neurosci. Res. 67, 618-624.
  23. Lu, Q., Paredes, M., Medina, M., Zhou, J., Cavallo, R., Peifer, M., Orecchio, L., and Kosik, K.S. (1999). delta-catenin, an adhesive junction-associated protein which promotes cell scattering. J. Cell Biol. 144, 519-532.
  24. Mangialasche, F., Solomon, A., Winblad, B., Mecocci, P., and Kivipelto, M. (2010). Alzheimer's disease: clinical trials and drug development. Lancet Neurol. 9, 702-716.
  25. Martinez, M.C., Ochiishi, T., Majewski, M., and Kosik, K.S. (2003). Dual regulation of neuronal morphogenesis by a delta-catenincortactin complex and Rho. J. Cell Biol. 162, 99-111.
  26. Medina, M., Marinescu, R.C., Overhauser, J., and Kosik, K.S. (2000). Hemizygosity of delta-catenin (CTNND2) is associated with severe mental retardation in cri-du-chat syndrome. Genomics 63, 157-164.
  27. Munoz, J.P., Huichalaf, C.H., Orellana, D., and Maccioni, R.B. (2007). cdk5 modulates beta- and delta-catenin/Pin1 interactions in neuronal cells. J. Cell. Biochem. 100, 738-749.
  28. Oh, M., Kim, H., Yang, I., Park, J.H., Cong, W.T., Baek, M.C., Bareiss, S., Ki, H., Lu, Q., No, J., et al. (2009). GSK-3 phosphorylates deltacatenin and negatively regulates its stability via ubiquitination/proteosome-mediated proteolysis. J. Biol. Chem. 284, 28579-28589.
  29. Patapoutian, A., and Reichardt, L.F. (2000). Roles of Wnt proteins in neural development and maintenance. Curr. Opin. Neurobiol. 10, 392-399.
  30. Pitsi, D., and Octave, J.N. (2004). Presenilin 1 stabilizes the C-terminal fragment of the amyloid precursor protein independently of gammasecretase activity. J. Biol. Chem. 279, 25333-25338.
  31. Rodova, M., Kelly, K.F., VanSaun, M., Daniel, J.M., and Werle, M.J. (2004). Regulation of the rapsyn promoter by kaiso and delta-catenin. Mol. Cell. Biol. 24, 7188-7196.
  32. Scheuner, D., Eckman, C., Jensen, M., Song, X., Citron, M., Suzuki, N., Bird, T.D., Hardy, J., Hutton, M., Kukull, W., et al. (1996). Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat. Med. 2, 864-870.
  33. Sorrentino, P., Iuliano, A., Polverino, A., Jacini, F., and Sorrentino, G. (2014). The dark sides of amyloid in Alzheimer's disease pathogenesis. FEBS Lett. 588, 641-652.
  34. Tanahashi, H., and Tabira, T. (1999). Isolation of human delta-catenin and its binding specificity with presenilin 1. Neuroreport 10, 563-568.
  35. Thinakaran, G., Borchelt, D.R., Lee, M.K., Slunt, H.H., Spitzer, L., Kim, G., Ratovitsky, T., Davenport, F., Nordstedt, C., Seeger, M., et al. (1996). Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 17, 181-190.
  36. Zhou, J., Liyanage, U., Medina, M., Ho, C., Simmons, A.D., Lovett, M., and Kosik, K.S. (1997). Presenilin 1 interaction in the brain with a novel member of the Armadillo family. Neuroreport 8, 2085-2090.