Startseite The role of ubiquitin proteasomal system and autophagy-lysosome pathway in Alzheimer’s disease
Artikel
Lizenziert
Nicht lizenziert Erfordert eine Authentifizierung

The role of ubiquitin proteasomal system and autophagy-lysosome pathway in Alzheimer’s disease

  • Yuan Zhang EMAIL logo , Xu Chen , Yanfang Zhao , Murugavel Ponnusamy und Ying Liu
Veröffentlicht/Copyright: 12. Juli 2017
Veröffentlichen auch Sie bei De Gruyter Brill

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder leading to dementia in the elderly population. AD is associated with the buildup of β-amyloid and tau, which aggregate into extracellular plaques and neurofibrillary tangles. Although the exact mechanism of pathological process of AD is unclear, the dysfunction of protein degradation mechanisms has been proposed to play an important role in AD. The cellular degradation of abnormal or misfolded proteins consists of three different mechanisms: the ubiquitin proteasomal system (UPS), autophagy-lysosomal pathway (ALP), and interaction of molecular chaperones with UPS or ALP. Any disturbance to these systems causes proteins to accumulate, resulting in pathological process of AD. In this review, we summarize the knowledge of protein degradation pathways in the pathogenesis of AD in light of the current literature. In the future, the regulation UPS or ALP machineries could be the cornerstones of the treatment of AD.

Acknowledgments

This work was supported by funding from the Shandong Provincial Natural Science Foundation of China (No. ZR2016CQ23) and the National Natural Science Foundation of China (No.31601194).

References

Blair, L.J., Sabbagh, J.J., and Dickey, C.A. (2014). Targeting Hsp90 and its co-chaperones to treat Alzheimer’s disease. Expert Opin. Ther. Targets 18, 1219–1232.10.1517/14728222.2014.943185Suche in Google Scholar PubMed PubMed Central

Caccamo, A., Magri, A., Medina, D.X., Wisely, E.V., Lopez-Aranda, M.F., Silva, A.J., and Oddo, S. (2013). mTOR regulates tau phosphorylation and degradation: implications for Alzheimer’s disease and other tauopathies. Aging Cell 12, 370–380.10.1111/acel.12057Suche in Google Scholar PubMed PubMed Central

Calvo-Rodriguez, M., de la Fuente, C., Garcia-Durillo, M., Garcia-Rodriguez, C., Villalobos, C., and Nunez, L. (2017). Aging and amyloid β oligomers enhance TLR4 expression, LPS-induced Ca2+ responses, and neuron cell death in cultured rat hippocampal neurons. J. Neuroinflammation 14, 24.10.1186/s12974-017-0802-0Suche in Google Scholar PubMed PubMed Central

Cheng, B., Anand, P., Kuang, A., Akhtar, F., and Scofield, V.L. (2016). N-Acetylcysteine in combination with IGF-1 enhances neuroprotection against proteasome dysfunction-induced neurotoxicity in SH-SY5Y cells. Parkinson’s Dis. 2016, 6564212.10.1155/2016/6564212Suche in Google Scholar PubMed PubMed Central

Choi, J., Gao, J., Kim, J., Hong, C., Kim, J., and Tontonoz, P. (2015). The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and Abeta amyloidosis. Sci. Transl. Med. 7, 314ra184.10.1126/scitranslmed.aad1904Suche in Google Scholar PubMed PubMed Central

Cripps, D., Thomas, S.N., Jeng, Y., Yang, F., Davies, P., and Yang, A.J. (2006). Alzheimer disease-specific conformation of hyperphosphorylated paired helical filament-Tau is polyubiquitinated through Lys-48, Lys-11, and Lys-6 ubiquitin conjugation. J. Biol. Chem. 281, 10825–10838.10.1074/jbc.M512786200Suche in Google Scholar PubMed

Friedman, L.G., Qureshi, Y.H., and Yu, W.H. (2015). Promoting autophagic clearance: viable therapeutic targets in Alzheimer’s disease. Neurotherapeutics 12, 94–108.10.1007/s13311-014-0320-zSuche in Google Scholar PubMed PubMed Central

Gadhave, K., Bolshette, N., Ahire, A., Pardeshi, R., Thakur, K., Trandafir, C., Istrate, A., Ahmed, S., Lahkar, M., Muresanu, D.F., et al. (2016). The ubiquitin proteasomal system: a potential target for the management of Alzheimer’s disease. J. Cell. Mol. Med. 20, 1392–1407.10.1111/jcmm.12817Suche in Google Scholar PubMed PubMed Central

Gentier, R.J. and van Leeuwen, F.W. (2015). Misframed ubiquitin and impaired protein quality control: an early event in Alzheimer’s disease. Front. Mol. Neurosci. 8, 47.10.3389/fnmol.2015.00047Suche in Google Scholar PubMed PubMed Central

Gentier, R.J., Verheijen, B.M., Zamboni, M., Stroeken, M.M., Hermes, D.J., Kusters, B., Steinbusch, H.W., Hopkins, D.A., and Van Leeuwen, F.W. (2015). Localization of mutant ubiquitin in the brain of a transgenic mouse line with proteasomal inhibition and its validation at specific sites in Alzheimer’s disease. Front. Neuroanat. 9, 26.10.3389/fnana.2015.00026Suche in Google Scholar PubMed PubMed Central

Gerakis, Y., Dunys, J., Bauer, C., and Checler, F. (2016). Abeta42 oligomers modulate beta-secretase through an XBP-1s-dependent pathway involving HRD1. Sci. Rep. 6, 37436.10.1038/srep37436Suche in Google Scholar PubMed PubMed Central

Guglielmotto, M., Monteleone, D., Boido, M., Piras, A., Giliberto, L., Borghi, R., Vercelli, A., Fornaro, M., Tabaton, M. and Tamagno, E. (2012). Aβ1-42-mediated down-regulation of Uch-L1 is dependent on NF-κB activation and impaired BACE1 lysosomal degradation. Aging Cell 11, 834–844.10.1111/j.1474-9726.2012.00854.xSuche in Google Scholar PubMed

Guo, J.L. and Lee, V.M. (2011). Seeding of normal Tau by pathological Tau conformers drives pathogenesis of Alzheimer-like tangles. J. Biol. Chem. 286, 15317–15331.10.1074/jbc.M110.209296Suche in Google Scholar PubMed PubMed Central

Hamano, T., Gendron, T.F., Causevic, E., Yen, S.H., Lin, W.L., Isidoro, C., Deture, M., and Ko, L.W. (2008). Autophagic-lysosomal perturbation enhances tau aggregation in transfectants with induced wild-type tau expression. Eur. J. Neurosci. 27, 1119–1130.10.1111/j.1460-9568.2008.06084.xSuche in Google Scholar PubMed

Hara, T., Nakamura, K., Matsui, M., Yamamoto, A., Nakahara, Y., Suzuki-Migishima, R., Yokoyama, M., Mishima, K., Saito, I., Okano, H., et al. (2006). Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889.10.1038/nature04724Suche in Google Scholar PubMed

Hong, L., Huang, H.C., and Jiang, Z.F. (2014). Relationship between amyloid-beta and the ubiquitin-proteasome system in Alzheimer’s disease. Neurol. Res. 36, 276–282.10.1179/1743132813Y.0000000288Suche in Google Scholar PubMed

Jansen, A.H., Reits, E.A., and Hol, E.M. (2014). The ubiquitin proteasome system in glia and its role in neurodegenerative diseases. Front. Mol. Neurosci. 7, 73.10.3389/fnmol.2014.00073Suche in Google Scholar PubMed PubMed Central

Jo, C., Gundemir, S., Pritchard, S., Jin, Y.N., Rahman, I., and Johnson, G.V. (2014). Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52. Nat. Commun. 5, 3496.10.1038/ncomms4496Suche in Google Scholar PubMed PubMed Central

Kaneko, M., Koike, H., Saito, R., Kitamura, Y., Okuma, Y., and Nomura, Y. (2010). Loss of HRD1-mediated protein degradation causes amyloid precursor protein accumulation and amyloid-β generation. J. Neurosci. 30, 3924–3932.10.1523/JNEUROSCI.2422-09.2010Suche in Google Scholar PubMed PubMed Central

Khandelwal, P.J., Herman, A.M., Hoe, H.S., Rebeck, G.W., and Moussa, C.E. (2011). Parkin mediates beclin-dependent autophagic clearance of defective mitochondria and ubiquitinated Abeta in AD models. Hum. Mol. Genet. 20, 2091–2102.10.1093/hmg/ddr091Suche in Google Scholar PubMed PubMed Central

Kim, S.I., Lee, W.K., Kang, S.S., Lee, S.Y., Jeong, M.J., Lee, H.J., Kim, S.S., Johnson, G.V., and Chun, W. (2011). Suppression of autophagy and activation of glycogen synthase kinase 3β facilitate the aggregate formation of tau. Korean J. Physiol. Pharmacol. 15, 107–114.10.4196/kjpp.2011.15.2.107Suche in Google Scholar PubMed PubMed Central

Kizilarslanoglu, M.C. and Ulger, Z. (2015). Role of autophagy in the pathogenesis of Alzheimer disease. Turk. J. Med. Sci. 45, 998–1003.10.3906/sag-1407-75Suche in Google Scholar PubMed

Lamoke, F., Mazzone, V., Persichini, T., Maraschi, A., Harris, M.B., Venema, R.C., Colasanti, M., Gliozzi, M., Muscoli, C., Bartoli, M., et al. (2015). Amyloid beta peptide-induced inhibition of endothelial nitric oxide production involves oxidative stress-mediated constitutive eNOS/HSP90 interaction and disruption of agonist-mediated Akt activation. J. Neuroinflammation 12, 84.10.1186/s12974-015-0304-xSuche in Google Scholar PubMed PubMed Central

Lecker, S.H., Goldberg, A.L., and Mitch, W.E. (2006). Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. J. Am. Soc. Nephrol. 17, 1807–1819.10.1681/ASN.2006010083Suche in Google Scholar PubMed

Lee, J.H., Yu, W.H., Kumar, A., Lee, S., Mohan, P.S., Peterhoff, C.M., Wolfe, D.M., Martinez-Vicente, M., Massey, A.C., Sovak, G., et al. (2010). Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141, 1146–1158.10.1016/j.cell.2010.05.008Suche in Google Scholar PubMed PubMed Central

Li, Q., Liu, Y., and Sun, M. (2017). Autophagy and Alzheimer’s disease. Cell. Mol. Neurobiol. 37, 377–388.10.1007/s10571-016-0386-8Suche in Google Scholar PubMed

Ling, D., Magallanes, M., and Salvaterra, P.M. (2014). Accumulation of amyloid-like Abeta1-42 in AEL (autophagy-endosomal-lysosomal) vesicles: potential implications for plaque biogenesis. ASN Neuro 6, e00139.10.1042/AN20130044Suche in Google Scholar PubMed PubMed Central

Liu, X., Hao, W., Qin, Y., Decker, Y., Wang, X., Burkart, M., Schotz, K., Menger, M.D., Fassbender, K., and Liu, Y. (2015a). Long-term treatment with Ginkgo biloba extract EGb 761 improves symptoms and pathology in a transgenic mouse model of Alzheimer’s disease. Brain Behav. Immun. 46, 121–131.10.1016/j.bbi.2015.01.011Suche in Google Scholar PubMed

Liu, Z., Li, T., Li, P., Wei, N., Zhao, Z., Liang, H., Ji, X., Chen, W., Xue, M., and Wei, J. (2015b). The ambiguous relationship of oxidative stress, Tau hyperphosphorylation, and autophagy dysfunction in Alzheimer’s disease. Oxid. Med. Cell. Longev. 2015, 352723.10.1155/2015/352723Suche in Google Scholar PubMed PubMed Central

Lonskaya, I., Shekoyan, A.R., Hebron, M.L., Desforges, N., Algarzae, N.K., and Moussa, C.E. (2013). Diminished parkin solubility and co-localization with intraneuronal amyloid-beta are associated with autophagic defects in Alzheimer’s disease. J. Alzheimer’s Dis. JAD 33, 231–247.10.3233/JAD-2012-121141Suche in Google Scholar PubMed

Lonskaya, I., Hebron, M.L., Desforges, N.M., Schachter, J.B., and Moussa, C.E. (2014). Nilotinib-induced autophagic changes increase endogenous parkin level and ubiquitination, leading to amyloid clearance. J. Mol. Med. 92, 373–386.10.1007/s00109-013-1112-3Suche in Google Scholar PubMed PubMed Central

Ma, L.Y., Lv, Y.L., Huo, K., Liu, J., Shang, S.H., Fei, Y.L., Li, Y.B., Zhao, B.Y., Wei, M., Deng, Y.N., et al. (2017). Autophagy-lysosome dysfunction is involved in Aβ deposition in STZ-induced diabetic rats. Behav. Brain Res. 320, 484–493.10.1016/j.bbr.2016.10.031Suche in Google Scholar PubMed

Matej, R., Rohan, Z., Holada, K., and Olejar, T. (2015). The contribution of proteinase-activated receptors to intracellular signaling, transcellular transport and autophagy in Alzheimer’s disease. Curr. Alzheimer Res. 12, 2–12.10.2174/1567205012666141218123202Suche in Google Scholar PubMed

McKinnon, C. and Tabrizi, S.J. (2014). The ubiquitin-proteasome system in neurodegeneration. Antioxid. Redox Signal. 21, 2302–2321.10.1089/ars.2013.5802Suche in Google Scholar PubMed

Myeku, N., Clelland, C.L., Emrani, S., Kukushkin, N.V., Yu, W.H., Goldberg, A.L., and Duff, K.E. (2016). Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling. Nat. Med. 22, 46–53.10.1038/nm.4011Suche in Google Scholar PubMed PubMed Central

Necchi, D., Lomoio, S., and Scherini, E. (2011). Dysfunction of the ubiquitin-proteasome system in the cerebellum of aging Ts65Dn mice. Exp. Neurol. 232, 114–118.10.1016/j.expneurol.2011.08.009Suche in Google Scholar PubMed

Nilsson, P. and Saido, T.C. (2014). Dual roles for autophagy: degradation and secretion of Alzheimer’s disease Abeta peptide. BioEssays 36, 570–578.10.1002/bies.201400002Suche in Google Scholar PubMed PubMed Central

Nixon, R.A. and Yang, D.S. (2011). Autophagy failure in Alzheimer’s disease—locating the primary defect. Neurobiol. Dis. 43, 38–45.10.1016/j.nbd.2011.01.021Suche in Google Scholar PubMed PubMed Central

Penke, B., Bogar, F., and Fulop, L. (2016). Protein folding and misfolding, endoplasmic reticulum stress in neurodegenerative diseases: in trace of novel drug targets. Curr. Protein Peptide Sci. 17, 169–182.10.2174/1389203716666151102104653Suche in Google Scholar PubMed

Pickford, F., Masliah, E., Britschgi, M., Lucin, K., Narasimhan, R., Jaeger, P.A., Small, S., Spencer, B., Rockenstein, E., Levine, B., et al. (2008). The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J. Clin. Invest. 118, 2190–2199.10.1172/JCI33585Suche in Google Scholar PubMed

Qu, A., Huang, F., Li, A., Yang, H., Zhou, H., Long, J., and Shi, L. (2017). The synergistic effect between KLVFF and self-assembly chaperones on both disaggregation of β-amyloid fibrils and reducing consequent toxicity. Chem. Commun. 53, 1289–1292.10.1039/C6CC07803FSuche in Google Scholar

Querfurth, H.W. and LaFerla, F.M. (2010). Alzheimer’s disease. N. Engl. J. Med. 362, 329–344.10.1056/NEJMra0909142Suche in Google Scholar PubMed

Renziehausen, J., Hiebel, C., Nagel, H., Kundu, A., Kins, S., Kogel, D., Behl, C., and Hajieva, P. (2015). The cleavage product of amyloid-β protein precursor sAβPPα modulates BAG3-dependent aggresome formation and enhances cellular proteasomal activity. J. Alzheimer’s Dis. 44, 879–896.10.3233/JAD-140600Suche in Google Scholar PubMed

Rosso, P., Moreno, S., Fracassi, A., Rocco, M.L., and Aloe, L. (2015). Nerve growth factor and autophagy: effect of nasal anti-NGF-antibodies administration on Ambra1 and Beclin-1 expression in rat brain. Growth Factors 33, 401–409.10.3109/08977194.2015.1122002Suche in Google Scholar PubMed

Saito, R., Kaneko, M., Okuma, Y., and Nomura, Y. (2010). Correlation between decrease in protein levels of ubiquitin ligase HRD1 and amyloid-beta production. J. Pharmacol. Sci. 113, 285–288.10.1254/jphs.10118SCSuche in Google Scholar PubMed

Sakono, M. and Zako, T. (2010). Amyloid oligomers: formation and toxicity of Abeta oligomers. FEBS J. 277, 1348–1358.10.1111/j.1742-4658.2010.07568.xSuche in Google Scholar PubMed

Sala, G., Marinig, D., Arosio, A., and Ferrarese, C. (2016). Role of chaperone-mediated autophagy dysfunctions in the pathogenesis of Parkinson’s disease. Front. Mol. Neurosci. 9, 157.10.3389/fnmol.2016.00157Suche in Google Scholar PubMed PubMed Central

Shen, J. and Kelleher, R.J., 3rd. (2007). The presenilin hypothesis of Alzheimer’s disease: evidence for a loss-of-function pathogenic mechanism. Proc. Natl. Acad. Sci. USA 104, 403–409.10.1073/pnas.0608332104Suche in Google Scholar PubMed PubMed Central

Singh, A.K. and Pati, U. (2015). CHIP stabilizes amyloid precursor protein via proteasomal degradation and p53-mediated trans-repression of β-secretase. Aging Cell 14, 595–604.10.1111/acel.12335Suche in Google Scholar PubMed PubMed Central

Son, S.M., Shin, H.J., Byun, J., Kook, S.Y., Moon, M., Chang, Y.J., and Mook-Jung, I. (2016). Metformin facilitates amyloid-beta generation by beta- and gamma-secretases via autophagy activation. J. Alzheimer’s Dis. 51, 1197–1208.10.3233/JAD-151200Suche in Google Scholar PubMed

Song, S., Kim, S.Y., Hong, Y.M., Jo, D.G., Lee, J.Y., Shim, S.M., Chung, C.W., Seo, S.J., Yoo, Y.J., Koh, J.Y., et al. (2003). Essential role of E2-25K/Hip-2 in mediating amyloid-beta neurotoxicity. Mol. Cell 12, 553–563.10.1016/j.molcel.2003.08.005Suche in Google Scholar PubMed

Song, S., Lee, H., Kam, T.I., Tai, M.L., Lee, J.Y., Noh, J.Y., Shim, S.M., Seo, S.J., Kong, Y.Y., Nakagawa, T., et al. (2008). E2-25K/Hip-2 regulates caspase-12 in ER stress-mediated Aβ neurotoxicity. J. Cell Biol. 182, 675–684.10.1083/jcb.200711066Suche in Google Scholar PubMed PubMed Central

Takashima, A. (2010). Tau aggregation is a therapeutic target for Alzheimer’s disease. Curr. Alzheimer Res. 7, 665–669.10.2174/156720510793611600Suche in Google Scholar PubMed

Tanaka, K. and Matsuda, N. (2014). Proteostasis and neurodegeneration: the roles of proteasomal degradation and autophagy. Biochim. Biophys. Acta 1843, 197–204.10.1016/j.bbamcr.2013.03.012Suche in Google Scholar PubMed

Tanokashira, D., Mamada, N., Yamamoto, F., Taniguchi, K., Tamaoka, A., Lakshmana, M.K., and Araki, W. (2017). The neurotoxicity of amyloid beta-protein oligomers is reversible in a primary neuron model. Mol. Brain 10, 4.10.1186/s13041-016-0284-5Suche in Google Scholar PubMed PubMed Central

Tramutola, A., Di Domenico, F., Barone, E., Perluigi, M., and Butterfield, D.A. (2016). It is all about (u)biquitin: role of altered ubiquitin-proteasome system and UCHL1 in Alzheimer disease. Oxid. Med. Cell. Longev. 2016, 2756068.10.1155/2016/2756068Suche in Google Scholar PubMed PubMed Central

Ugalde, C.L., Finkelstein, D.I., Lawson, V.A., and Hill, A.F. (2016). Pathogenic mechanisms of prion protein, amyloid-beta and alpha-synuclein misfolding: the prion concept and neurotoxicity of protein oligomers. J. Neurochem. 139, 162–180.10.1111/jnc.13772Suche in Google Scholar PubMed

Viola, K.L. and Klein, W.L. (2015). Amyloid beta oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis. Acta Neuropathol. 129, 183–206.10.1007/s00401-015-1386-3Suche in Google Scholar PubMed PubMed Central

Vriend, J., Ghavami, S., and Marzban, H. (2015). The role of the ubiquitin proteasome system in cerebellar development and medulloblastoma. Mol. Brain 8, 64.10.1186/s13041-015-0155-5Suche in Google Scholar PubMed PubMed Central

Wang, Y. and Mandelkow, E. (2012). Degradation of tau protein by autophagy and proteasomal pathways. Biochem. Soc. Trans. 40, 644–652.10.1042/BST20120071Suche in Google Scholar PubMed

Wang, C., Zhang, X., Teng, Z., Zhang, T., and Li, Y. (2014). Downregulation of PI3K/Akt/mTOR signaling pathway in curcumin-induced autophagy in APP/PS1 double transgenic mice. Eur. J. Pharmacol. 740, 312–320.10.1016/j.ejphar.2014.06.051Suche in Google Scholar PubMed

Wolfe, D.M., Lee, J.H., Kumar, A., Lee, S., Orenstein, S.J., and Nixon, R.A. (2013). Autophagy failure in Alzheimer’s disease and the role of defective lysosomal acidification. Eur. J. Neurosci. 37, 1949–1961.10.1111/ejn.12169Suche in Google Scholar PubMed PubMed Central

Xue, X., Wang, L.R., Sato, Y., Jiang, Y., Berg, M., Yang, D.S., Nixon, R.A., and Liang, X.J. (2014). Single-walled carbon nanotubes alleviate autophagic/lysosomal defects in primary glia from a mouse model of Alzheimer’s disease. Nano Lett. 14, 5110–5117.10.1021/nl501839qSuche in Google Scholar PubMed PubMed Central

Yurinskaya, M.M., Mit’kevich, V.A., Evgen’ev, M.B., Makarov, A.A., and Vinokurov, M.G. (2016). Heat-shock protein HSP70 reduces the secretion of TNFα by neuroblastoma cells and human monocytes induced with beta-amyloid peptides. Mol. Biol. 50, 1053–1056.10.1134/S0026893316060236Suche in Google Scholar

Zhang, M., Deng, Y., Luo, Y., Zhang, S., Zou, H., Cai, F., Wada, K., and Song, W. (2012a). Control of BACE1 degradation and APP processing by ubiquitin carboxyl-terminal hydrolase L1. J. Neurochem. 120, 1129–1138.10.1111/j.1471-4159.2011.07644.xSuche in Google Scholar PubMed

Zhang, X., Garbett, K., Veeraraghavalu, K., Wilburn, B., Gilmore, R., Mirnics, K., and Sisodia, S.S. (2012b). A role for presenilins in autophagy revisited: normal acidification of lysosomes in cells lacking PSEN1 and PSEN2. J. Neurosci. 32, 8633–8648.10.1523/JNEUROSCI.0556-12.2012Suche in Google Scholar PubMed PubMed Central

Zhang, M., Cai, F., Zhang, S., Zhang, S., and Song, W. (2014). Overexpression of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) delays Alzheimer’s progression in vivo. Sci. Rep. 4, 7298.10.1038/srep07298Suche in Google Scholar PubMed PubMed Central

Received: 2017-2-16
Accepted: 2017-4-21
Published Online: 2017-7-12
Published in Print: 2017-11-27

©2017 Walter de Gruyter GmbH, Berlin/Boston

Heruntergeladen am 26.11.2025 von https://www.degruyterbrill.com/document/doi/10.1515/revneuro-2017-0013/pdf
Button zum nach oben scrollen