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

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.

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

References

[1] Aguzzi, A., and Haass, C. (2003). Games played by rogue proteins in prion disorders and Alzheimer’s disease. Science 302, 814-818 .14593165
[2] Beyreuther, K., Bush, A.I., Dyrks, T., Hilbich, C., K?nig, G., M?nning, U., Multhaup, G., Prior, R., Rumble, B., Schubert, W., (1991). Mechanisms of amyloid deposition in Alzheimer’s disease. Ann N Y Acad Sci 640, 129-139 . 1776729
[3] Beyreuther, K., Multhaup, G., M?nning, U., Sandbrink, R., Beher, D., Hesse, L., Small, D.H., and Masters, C.L. (1996). Regulation of APP expression, biogenesis and metabolism by extracellular matrix and cytokines. Ann N Y Acad Sci 777, 74-76 .8624129
[4] Cao, X., and Südhof, T.C. (2001). A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60. Science 293, 115-120 .11441186
[5] Cataldo, A.M., Paskevich, P.A., Kominami, E., and Nixon, R.A. (1991). Lysosomal hydrolases of different classes are abnormally distributed in brains of patients with Alzheimer disease. Proc Natl Acad Sci U S A 88, 10998-11002 .1837142
[6] Chen, M., and Yankner, B.A. (1991). An antibody to beta amyloid and the amyloid precursor protein inhibits cell-substratum adhesion in many mammalian cell types. Neurosci Lett 125, 223-226 .1715534
[7] Coulson, E.J., Barrett, G.L., Storey, E., Bartlett, P.F., Beyreuther, K., and Masters, C.L. (1997). Down-regulation of the amyloid protein precursor of Alzheimer’s disease by antisense oligonucleotides reduces neuronal adhesion to specific substrata. Brain Res 770, 72-80 .9372205
[8] Dash, P.K., and Moore, A.N. (1993). Inhibitors of endocytosis, endosome fusion, and lysosomal processing inhibit the intracellular proteolysis of the amyloid precursor protein. Neurosci Lett 164, 183-186 .8152599
[9] Golde, T.E., Estus, S., Younkin, L.H., Selkoe, D.J., and Younkin, S.G. (1992). Processing of the amyloid protein precursor to potentially amyloidogenic derivatives. Science 255, 728-730 .1738847
[10] Hedera, P., and Turner, R.S. (2002). Inherited dementias.[vii.] Neurol Clin 20, 779-808, vii . 12432830
[11] Jin, L.W., Ninomiya, H., Roch, J.M., Schubert, D., Masliah, E., Otero, D.A., and Saitoh, T. (1994). Peptides containing the RERMS sequence of amyloid beta/A4 protein precursor bind cell surface and promote neurite extension. J Neurosci 14, 5461-5470 .8083748
[12] Kaden, D., Voigt, P., Munter, L.M., Bobowski, K.D., Schaefer, M., and Multhaup, G. (2009). Subcellular localization and dimerization of APLP1 are strikingly different from APP and APLP2. J Cell Sci 122, 368-377 . 19126676
[13] Kessel, D., and Oleinick, N.L. (2009). Initiation of autophagy by photodynamic therapy. Methods Enzymol 453, 1-16 .19216899
[14] Liang, C.C., Wang, C., Peng, X., Gan, B., and Guan, J.L. (2010). Neural-specific deletion of FIP200 leads to cerebellar degeneration caused by increased neuronal death and axon degeneration. J Biol Chem 285, 3499-3509 .19940130
[15] Mizushima, N. (2005). A(beta) generation in autophagic vacuoles. J Cell Biol 171, 15-17 .16216920
[16] Muresan, Z., and Muresan, V. (2005). c-Jun NH2-terminal kinase-interacting protein-3 facilitates phosphorylation and controls localization of amyloid-beta precursor protein. J Neurosci 25, 3741-3751 .15829626
[17] Shimizu, S., Konishi, A., Nishida, Y., Mizuta, T., Nishina, H., Yamamoto, A., and Tsujimoto, Y. (2010). Involvement of JNK in the regulation of autophagic cell death. Oncogene 29, 2070-2082 .20101227
[18] Soba, P., Eggert, S., Wagner, K., Zentgraf, H., Siehl, K., Kreger, S., L?wer, A., Langer, A., Merdes, G., Paro, R., (2005). Homo- and heterodimerization of APP family members promotes intercellular adhesion. EMBO J 24, 3624-3634 .16193067
[19] Tanzi, R.E., McClatchey, A.I., Lamperti, E.D., Villa-Komaroff, L., Gusella, J.F., and Neve, R.L. (1988). Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer’s disease. Nature 331, 528-530 .2893290
[20] Zhang, L., Gao, X., Wen, J., Ning, Y., and Chen, Y.G. (2006). Dapper 1 antagonizes Wnt signaling by promoting dishevelled degradation. J Biol Chem 281, 8607-8612 .16446366
[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 {beta}-catenin Degradation. Mol Biol 22 ,1617-1624 .
[22] Zhang, L., Zhou, H., Su, Y., Sun, Z., Zhang, H., Zhang, L., Zhang, Y., Ning, Y., Chen, Y.G., and Meng, A. (2004). Zebrafish Dpr2 inhibits mesoderm induction by promoting degradation of nodal receptors. Science 306, 114-117 .15459392
[23] Zhou, F., Zhang, L., Wang, A., Song, B., Gong, K., Zhang, L., Hu, M., Zhang, X., Zhao, N., and Gong, Y. (2008). The association of GSK3 beta with E2F1 facilitates nerve growth factor-induced neural cell differentiation. J Biol Chem 283, 14506-14515 .18367454