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. 2011 May 28;2(5):377–383. doi: 10.1007/s13238-011-1047-9

APP and APLP1 are degraded through autophagy in response to proteasome inhibition in neuronal cells

Fangfang Zhou 1,2, Theo van Laar 2, Huizhe Huang 1,✉, Long Zhang 2,✉
PMCID: PMC4875337  PMID: 21626267

Abstract

Amyloid beta (Aβ) precursor protein (APP) is a key protein in the pathogenesis of Alzheimer’s disease (AD). Both APP and its paralogue APLP1 (amyloid beta precursor-like protein 1) have multiple functions in cell adhesion and proliferation. Previously it was thought that autophagy is a novel beta-amyloid peptide (Aβ)-generating pathway activated in AD. However, the protein proteolysis of APLP1 is still largely unknown. The present study shows that APLP1 is rapidly degraded in neuronal cells in response to stresses, such as proteasome inhibition. Activation of the endoplasmic reticulum (ER) stress by proteasome inhibitors induces autophagy, causing reduction of mature APLP1/APP. Blocking autophagy or JNK stress kinase rescues the protein expression for both APP and APLP1. Therefore, our results suggest that APP/APLP1 is degraded through autophagy and the APLP1 proteolysis is mainly mediated by autophagy-lysosome pathway.

Keywords: amyloid beta precursor-like protein 1 (APLP1), amyloid precursor protein (APP), proteasome inhibition, endoplasmic reticulum stress, autophagy, neuronal cells

Contributor Information

Huizhe Huang, Email: devbiology@cqmu.edu.cn.

Long Zhang, Email: L.zhang@lumc.nl.

References

  1. Aguzzi A., Haass C. Games played by rogue proteins in prion disorders and Alzheimer’s disease. Science. 2003;302:814–818. doi: 10.1126/science.1087348. [DOI] [PubMed] [Google Scholar]
  2. Beyreuther K., Bush A.I., Dyrks T., Hilbich C., König G., Mönning U., Multhaup G., Prior R., Rumble B., Schubert W., et al. Mechanisms of amyloid deposition in Alzheimer’s disease. Ann N Y Acad Sci. 1991;640:129–139. doi: 10.1111/j.1749-6632.1991.tb00204.x. [DOI] [PubMed] [Google Scholar]
  3. Beyreuther K., Multhaup G., Mönning U., Sandbrink R., Beher D., Hesse L., Small D.H., Masters C.L. Regulation of APP expression, biogenesis and metabolism by extracellular matrix and cytokines. Ann N Y Acad Sci. 1996;777:74–76. doi: 10.1111/j.1749-6632.1996.tb34403.x. [DOI] [PubMed] [Google Scholar]
  4. Cao X., Südhof T.C. A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60. Science. 2001;293:115–120. doi: 10.1126/science.1058783. [DOI] [PubMed] [Google Scholar]
  5. Cataldo A.M., Paskevich P.A., Kominami E., Nixon R.A. Lysosomal hydrolases of different classes are abnormally distributed in brains of patients with Alzheimer disease. Proc Natl Acad Sci U S A. 1991;88:10998–11002. doi: 10.1073/pnas.88.24.10998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chen M., Yankner B.A. An antibody to beta amyloid and the amyloid precursor protein inhibits cell-substratum adhesion in many mammalian cell types. Neurosci Lett. 1991;125:223–226. doi: 10.1016/0304-3940(91)90034-Q. [DOI] [PubMed] [Google Scholar]
  7. Coulson E.J., Barrett G.L., Storey E., Bartlett P.F., Beyreuther K., Masters C.L. Down-regulation of the amyloid protein precursor of Alzheimer’s disease by antisense oligonucleotides reduces neuronal adhesion to specific substrata. Brain Res. 1997;770:72–80. doi: 10.1016/S0006-8993(97)00757-9. [DOI] [PubMed] [Google Scholar]
  8. Dash P.K., Moore A.N. Inhibitors of endocytosis, endosome fusion, and lysosomal processing inhibit the intracellular proteolysis of the amyloid precursor protein. Neurosci Lett. 1993;164:183–186. doi: 10.1016/0304-3940(93)90887-Q. [DOI] [PubMed] [Google Scholar]
  9. Golde T.E., Estus S., Younkin L.H., Selkoe D.J., Younkin S.G. Processing of the amyloid protein precursor to potentially amyloidogenic derivatives. Science. 1992;255:728–730. doi: 10.1126/science.1738847. [DOI] [PubMed] [Google Scholar]
  10. Hedera P., Turner R.S. Inherited dementias. Neurol Clin. 2002;20:779–808. doi: 10.1016/S0733-8619(01)00020-2. [DOI] [PubMed] [Google Scholar]
  11. Jin L.W., Ninomiya H., Roch J.M., Schubert D., Masliah E., Otero D.A., Saitoh T. Peptides containing the RERMS sequence of amyloid beta/A4 protein precursor bind cell surface and promote neurite extension. J Neurosci. 1994;14:5461–5470. doi: 10.1523/JNEUROSCI.14-09-05461.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kaden D., Voigt P., Munter L.M., Bobowski K.D., Schaefer M., Multhaup G. Subcellular localization and dimerization of APLP1 are strikingly different from APP and APLP2. J Cell Sci. 2009;122:368–377. doi: 10.1242/jcs.034058. [DOI] [PubMed] [Google Scholar]
  13. Kessel D., Oleinick N.L. Initiation of autophagy by photodynamic therapy. Methods Enzymol. 2009;453:1–16. doi: 10.1016/S0076-6879(08)04001-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Liang C.C., Wang C., Peng X., Gan B., Guan J.L. Neural-specific deletion of FIP200 leads to cerebellar degeneration caused by increased neuronal death and axon degeneration. J Biol Chem. 2010;285:3499–3509. doi: 10.1074/jbc.M109.072389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Mizushima N. A(beta) generation in autophagic vacuoles. J Cell Biol. 2005;171:15–17. doi: 10.1083/jcb.200508097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Muresan Z., Muresan V. c-Jun NH2-terminal kinaseinteracting protein-3 facilitates phosphorylation and controls localization of amyloid-beta precursor protein. J Neurosci. 2005;25:3741–3751. doi: 10.1523/JNEUROSCI.0152-05.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Shimizu S., Konishi A., Nishida Y., Mizuta T., Nishina H., Yamamoto A., Tsujimoto Y. Involvement of JNK in the regulation of autophagic cell death. Oncogene. 2010;29:2070–2082. doi: 10.1038/onc.2009.487. [DOI] [PubMed] [Google Scholar]
  18. Soba P., Eggert S., Wagner K., Zentgraf H., Siehl K., Kreger S., Löwer A., Langer A., Merdes G., Paro R., et al. Homoand heterodimerization of APP family members promotes intercellular adhesion. EMBO J. 2005;24:3624–3634. doi: 10.1038/sj.emboj.7600824. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Tanzi R.E., McClatchey A.I., Lamperti E.D., Villa-Komaroff L., Gusella J.F., Neve R.L. Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer’s disease. Nature. 1988;331:528–530. doi: 10.1038/331528a0. [DOI] [PubMed] [Google Scholar]
  20. Zhang L., Gao X., Wen J., Ning Y., Chen Y.G. Dapper 1 antagonizes Wnt signaling by promoting dishevelled degradation. J Biol Chem. 2006;281:8607–8612. doi: 10.1074/jbc.M600274200. [DOI] [PubMed] [Google Scholar]
  21. Zhang, L., Zhou, F., van Laar, T., Zhang, J., van Dam, H., and Ten Dijke, P. (2011). Fas-associated factor 1 Antagonizes Wnt Signaling by Promoting ta-catenin Degradation. Mol Biol 22, 1617–1624. [DOI] [PMC free article] [PubMed]
  22. Zhang L., Zhou H., Su Y., Sun Z., Zhang H., Zhang L., Zhang Y., Ning Y., Chen Y.G., Meng A. Zebrafish Dpr2 inhibits mesoderm induction by promoting degradation of nodal receptors. Science. 2004;306:114–117. doi: 10.1126/science.1100569. [DOI] [PubMed] [Google Scholar]
  23. Zhou F., Zhang L., Wang A., Song B., Gong K., Zhang L., Hu M., Zhang X., Zhao N., Gong Y. The association of GSK3 beta with E2F1 facilitates nerve growth factor-induced neural cell differentiation. J Biol Chem. 2008;283:14506–14515. doi: 10.1074/jbc.M706136200. [DOI] [PubMed] [Google Scholar]

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