{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T13:09:43Z","timestamp":1793970583177,"version":"4.8.0"},"reference-count":83,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,2,4]],"date-time":"2019-02-04T00:00:00Z","timestamp":1549238400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,2,4]],"date-time":"2019-02-04T00:00:00Z","timestamp":1549238400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Intraneuronal accumulation of amyloid-\u03b2(1\u201342) (A\u03b21\u201342) is one of the earliest signs of Alzheimer\u2019s disease (AD). Cell surface heparan sulfate proteoglycans (HSPGs) have profound influence on the cellular uptake of A\u03b21\u201342 by mediating its attachment and subsequent internalization into the cells. Colocalization of amyloid plaques with members of the syndecan family of HSPGs, along with the increased expression of syndecan-3 and -4 have already been reported in postmortem AD brains. Considering the growing evidence on the involvement of syndecans in the pathogenesis of AD, we analyzed the contribution of syndecans to cellular uptake and fibrillation of A\u03b21\u201342. Among syndecans, the neuron specific syndecan-3 isoform increased cellular uptake of A\u03b21\u201342 the most. Kinetics of A\u03b21\u201342 uptake also proved to be fairly different among SDC family members: syndecan-3 increased A\u03b21\u201342 uptake from the earliest time points, while other syndecans facilitated A\u03b21\u201342 internalization at a slower pace. Internalized A\u03b21\u201342 colocalized with syndecans and flotillins, highlighting the role of lipid-rafts in syndecan-mediated uptake. Syndecan-3 and 4 also triggered fibrillation of A\u03b21\u201342, further emphasizing the pathophysiological relevance of syndecans in plaque formation. Overall our data highlight syndecans, especially the neuron-specific syndecan-3 isoform, as important players in amyloid pathology and show that syndecans, regardless of cell type, facilitate key molecular events in neurodegeneration.<\/jats:p>","DOI":"10.1038\/s41598-018-37476-9","type":"journal-article","created":{"date-parts":[[2019,2,4]],"date-time":"2019-02-04T11:04:09Z","timestamp":1549278249000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Contribution of syndecans to cellular internalization and fibrillation of amyloid-\u03b2(1\u201342)"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6035-4009","authenticated-orcid":false,"given":"Tam\u00e1s","family":"Letoha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anett","family":"Hud\u00e1k","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erzs\u00e9bet","family":"Kusz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alad\u00e1r","family":"Pettk\u00f3-Szandtner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ildik\u00f3","family":"Domonkos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katalin","family":"J\u00f3svay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9012-6720","authenticated-orcid":false,"given":"Martin","family":"Hofmann-Apitius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e1szl\u00f3","family":"Szil\u00e1k","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,2,4]]},"reference":[{"key":"37476_CR1","doi-asserted-by":"publisher","first-page":"518","DOI":"10.3399\/bjgp12X656739","volume":"62","author":"M Lakhani","year":"2012","unstructured":"Lakhani, M. 21st century health services challenges for an ageing population. The British journal of general practice: the journal of the Royal College of General Practitioners 62, 518, https:\/\/doi.org\/10.3399\/bjgp12X656739 (2012).","journal-title":"The British journal of general practice: the journal of the Royal College of General Practitioners"},{"key":"37476_CR2","doi-asserted-by":"publisher","first-page":"1196","DOI":"10.1016\/S0140-6736(09)61460-4","volume":"374","author":"K Christensen","year":"2009","unstructured":"Christensen, K., Doblhammer, G., Rau, R. & Vaupel, J. W. Ageing populations: the challenges ahead. Lancet 374, 1196\u20131208, https:\/\/doi.org\/10.1016\/S0140-6736(09)61460-4 (2009).","journal-title":"Lancet"},{"key":"37476_CR3","doi-asserted-by":"publisher","first-page":"e1002275","DOI":"10.1371\/journal.pmed.1002275","volume":"14","author":"C Brayne","year":"2017","unstructured":"Brayne, C. & Miller, B. Dementia and aging populations-A global priority for contextualized research and health policy. Plos medicine 14, e1002275, https:\/\/doi.org\/10.1371\/journal.pmed.1002275 (2017).","journal-title":"Plos medicine"},{"key":"37476_CR4","doi-asserted-by":"publisher","first-page":"b158","DOI":"10.1136\/bmj.b158","volume":"338","author":"A Burns","year":"2009","unstructured":"Burns, A. & Iliffe, S. Alzheimer\u2019s disease. Bmj 338, b158, https:\/\/doi.org\/10.1136\/bmj.b158 (2009).","journal-title":"Bmj"},{"key":"37476_CR5","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1016\/j.jalz.2016.03.001","volume":"12","author":"A Alzheimer\u2019s","year":"2016","unstructured":"Alzheimer\u2019s, A. Alzheimer\u2019s disease facts and figures. Alzheimer\u2019s & dementia: the journal of the Alzheimer\u2019s Association 12, 459\u2013509 (2016).","journal-title":"Alzheimer\u2019s & dementia: the journal of the Alzheimer\u2019s Association"},{"key":"37476_CR6","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1016\/j.ncl.2016.06.009","volume":"34","author":"RA Hickman","year":"2016","unstructured":"Hickman, R. A., Faustin, A. & Wisniewski, T. Alzheimer Disease and Its Growing Epidemic: Risk Factors, Biomarkers, and the Urgent Need for Therapeutics. Neurologic clinics 34, 941\u2013953, https:\/\/doi.org\/10.1016\/j.ncl.2016.06.009 (2016).","journal-title":"Neurologic clinics"},{"key":"37476_CR7","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1038\/nrd4749","volume":"14","author":"X Qian","year":"2015","unstructured":"Qian, X., Hamad, B. & Dias-Lalcaca, G. The Alzheimer disease market. Nature reviews. Drug discovery 14, 675\u2013676, https:\/\/doi.org\/10.1038\/nrd4749 (2015).","journal-title":"Nature reviews. Drug discovery"},{"key":"37476_CR8","doi-asserted-by":"publisher","first-page":"a006189","DOI":"10.1101\/cshperspect.a006189","volume":"1","author":"A Serrano-Pozo","year":"2011","unstructured":"Serrano-Pozo, A., Frosch, M. P., Masliah, E. & Hyman, B. T. Neuropathological alterations in Alzheimer disease. Cold Spring Harbor perspectives in medicine 1, a006189, https:\/\/doi.org\/10.1101\/cshperspect.a006189 (2011).","journal-title":"Cold Spring Harbor perspectives in medicine"},{"key":"37476_CR9","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-014-0135-5","volume":"2","author":"GP Morris","year":"2014","unstructured":"Morris, G. P., Clark, I. A. & Vissel, B. Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer\u2019s disease. Acta neuropathologica communications 2, 135, https:\/\/doi.org\/10.1186\/s40478-014-0135-5 (2014).","journal-title":"Acta neuropathologica communications"},{"key":"37476_CR10","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1111\/febs.14004","volume":"284","author":"J Hardy","year":"2017","unstructured":"Hardy, J. The discovery of Alzheimer-causing mutations in the APP gene and the formulation of the \u201camyloid cascade hypothesis\u201d. The FEBS journal 284, 1040\u20131044, https:\/\/doi.org\/10.1111\/febs.14004 (2017).","journal-title":"The FEBS journal"},{"key":"37476_CR11","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1126\/scitranslmed.aad3650","volume":"8","author":"CC Liu","year":"2016","unstructured":"Liu, C. C. et al. Neuronal heparan sulfates promote amyloid pathology by modulating brain amyloid-beta clearance and aggregation in Alzheimer\u2019s disease. Science translational medicine 8, 332\u2013344, https:\/\/doi.org\/10.1126\/scitranslmed.aad3650 (2016).","journal-title":"Science translational medicine"},{"key":"37476_CR12","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1038\/nrneurol.2015.119","volume":"11","author":"JM Tarasoff-Conway","year":"2015","unstructured":"Tarasoff-Conway, J. M. et al. Clearance systems in the brain-implications for Alzheimer disease. Nature reviews. Neurology 11, 457\u2013470, https:\/\/doi.org\/10.1038\/nrneurol.2015.119 (2015).","journal-title":"Nature reviews. Neurology"},{"key":"37476_CR13","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-02227-9","volume":"7","author":"E Wesen","year":"2017","unstructured":"Wesen, E., Jeffries, G. D. M., Matson Dzebo, M. & Esbjorner, E. K. Endocytic uptake of monomeric amyloid-beta peptides is clathrin- and dynamin-independent and results in selective accumulation of Abeta(1\u201342) compared to Abeta(1\u201340). Scientific reports 7, 2021, https:\/\/doi.org\/10.1038\/s41598-017-02227-9 (2017).","journal-title":"Scientific reports"},{"key":"37476_CR14","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1016\/j.neurobiolaging.2004.09.018","volume":"26","author":"RA Nixon","year":"2005","unstructured":"Nixon, R. A. Endosome function and dysfunction in Alzheimer\u2019s disease and other neurodegenerative diseases. Neurobiology of aging 26, 373\u2013382, https:\/\/doi.org\/10.1016\/j.neurobiolaging.2004.09.018 (2005).","journal-title":"Neurobiology of aging"},{"key":"37476_CR15","doi-asserted-by":"publisher","first-page":"1571","DOI":"10.1001\/jama.283.12.1571","volume":"283","author":"J Naslund","year":"2000","unstructured":"Naslund, J. et al. Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. Jama 283, 1571\u20131577 (2000).","journal-title":"Jama"},{"key":"37476_CR16","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.1016\/j.neurobiolaging.2006.06.019","volume":"28","author":"M Knobloch","year":"2007","unstructured":"Knobloch, M., Konietzko, U., Krebs, D. C. & Nitsch, R. M. Intracellular Abeta and cognitive deficits precede beta-amyloid deposition in transgenic arcAbeta mice. Neurobiology of aging 28, 1297\u20131306, https:\/\/doi.org\/10.1016\/j.neurobiolaging.2006.06.019 (2007).","journal-title":"Neurobiology of aging"},{"key":"37476_CR17","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1016\/j.bbamcr.2008.12.001","volume":"1793","author":"A Ballabio","year":"2009","unstructured":"Ballabio, A. & Gieselmann, V. Lysosomal disorders: from storage to cellular damage. Biochim Biophys Acta 1793, 684\u2013696, https:\/\/doi.org\/10.1016\/j.bbamcr.2008.12.001 (2009).","journal-title":"Biochim Biophys Acta"},{"key":"37476_CR18","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/S0002-9440(10)64700-1","volume":"156","author":"GK Gouras","year":"2000","unstructured":"Gouras, G. K. et al. Intraneuronal Abeta42 accumulation in human brain. The American journal of pathology 156, 15\u201320 (2000).","journal-title":"The American journal of pathology"},{"key":"37476_CR19","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1016\/S0304-3940(01)01876-6","volume":"306","author":"O Wirths","year":"2001","unstructured":"Wirths, O. et al. Intraneuronal Abeta accumulation precedes plaque formation in beta-amyloid precursor protein and presenilin-1 double-transgenic mice. Neuroscience letters 306, 116\u2013120 (2001).","journal-title":"Neuroscience letters"},{"key":"37476_CR20","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.nbd.2013.12.019","volume":"65","author":"J Domert","year":"2014","unstructured":"Domert, J. et al. Spreading of amyloid-beta peptides via neuritic cell-to-cell transfer is dependent on insufficient cellular clearance. Neurobiology of disease 65, 82\u201392, https:\/\/doi.org\/10.1016\/j.nbd.2013.12.019 (2014).","journal-title":"Neurobiology of disease"},{"key":"37476_CR21","doi-asserted-by":"publisher","first-page":"d327","DOI":"10.2741\/A277","volume":"3","author":"K Fukuchi","year":"1998","unstructured":"Fukuchi, K., Hart, M. & Li, L. Alzheimer\u2019s disease and heparan sulfate proteoglycan. Frontiers in bioscience: a journal and virtual library 3, d327\u2013337 (1998).","journal-title":"Frontiers in bioscience: a journal and virtual library"},{"key":"37476_CR22","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1111\/j.1749-6632.1996.tb34439.x","volume":"777","author":"DH Small","year":"1996","unstructured":"Small, D. H. et al. The role of heparan sulfate proteoglycans in the pathogenesis of Alzheimer\u2019s disease. Annals of the New York Academy of Sciences 777, 316\u2013321 (1996).","journal-title":"Annals of the New York Academy of Sciences"},{"key":"37476_CR23","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1016\/S1474-4422(03)00484-8","volume":"2","author":"J van Horssen","year":"2003","unstructured":"van Horssen, J., Wesseling, P., van den Heuvel, L. P., de Waal, R. M. & Verbeek, M. M. Heparan sulphate proteoglycans in Alzheimer\u2019s disease and amyloid-related disorders. The Lancet. Neurology 2, 482\u2013492 (2003).","journal-title":"The Lancet. Neurology"},{"key":"37476_CR24","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/j.jocn.2008.04.009","volume":"16","author":"H Shimizu","year":"2009","unstructured":"Shimizu, H., Ghazizadeh, M., Sato, S., Oguro, T. & Kawanami, O. Interaction between beta-amyloid protein and heparan sulfate proteoglycans from the cerebral capillary basement membrane in Alzheimer\u2019s disease. Journal of clinical neuroscience: official journal of the Neurosurgical Society of Australasia 16, 277\u2013282, https:\/\/doi.org\/10.1016\/j.jocn.2008.04.009 (2009).","journal-title":"Journal of clinical neuroscience: official journal of the Neurosurgical Society of Australasia"},{"key":"37476_CR25","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1007\/s00401-009-0577-1","volume":"119","author":"IB Bruinsma","year":"2010","unstructured":"Bruinsma, I. B. et al. Sulfation of heparan sulfate associated with amyloid-beta plaques in patients with Alzheimer\u2019s disease. Acta neuropathologica 119, 211\u2013220, https:\/\/doi.org\/10.1007\/s00401-009-0577-1 (2010).","journal-title":"Acta neuropathologica"},{"key":"37476_CR26","first-page":"456","volume":"133","author":"AD Snow","year":"1988","unstructured":"Snow, A. D. et al. The presence of heparan sulfate proteoglycans in the neuritic plaques and congophilic angiopathy in Alzheimer\u2019s disease. The American journal of pathology 133, 456\u2013463 (1988).","journal-title":"The American journal of pathology"},{"key":"37476_CR27","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/0006-8993(90)91111-S","volume":"508","author":"LS Perlmutter","year":"1990","unstructured":"Perlmutter, L. S., Chui, H. C., Saperia, D. & Athanikar, J. Microangiopathy and the colocalization of heparan sulfate proteoglycan with amyloid in senile plaques of Alzheimer\u2019s disease. Brain research 508, 13\u201319 (1990).","journal-title":"Brain research"},{"key":"37476_CR28","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1016\/0306-4522(92)90521-3","volume":"51","author":"JH Su","year":"1992","unstructured":"Su, J. H., Cummings, B. J. & Cotman, C. W. Localization of heparan sulfate glycosaminoglycan and proteoglycan core protein in aged brain and Alzheimer\u2019s disease. Neuroscience 51, 801\u2013813 (1992).","journal-title":"Neuroscience"},{"key":"37476_CR29","first-page":"308","volume":"4","author":"D Van Gool","year":"1993","unstructured":"Van Gool, D., David, G., Lammens, M., Baro, F. & Dom, R. Heparan sulfate expression patterns in the amyloid deposits of patients with Alzheimer\u2019s and Lewy body type dementia. Dementia 4, 308\u2013314 (1993).","journal-title":"Dementia"},{"key":"37476_CR30","doi-asserted-by":"publisher","first-page":"2187","DOI":"10.1021\/acs.jpcb.5b12235","volume":"120","author":"K Nguyen","year":"2016","unstructured":"Nguyen, K. & Rabenstein, D. L. Interaction of the Heparin-Binding Consensus Sequence of beta-Amyloid Peptides with Heparin and Heparin-Derived Oligosaccharides. The journal of physical chemistry. B 120, 2187\u20132197, https:\/\/doi.org\/10.1021\/acs.jpcb.5b12235 (2016).","journal-title":"The journal of physical chemistry. B"},{"key":"37476_CR31","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1002\/jmr.300080403","volume":"8","author":"G Multhaup","year":"1995","unstructured":"Multhaup, G., Mechler, H. & Masters, C. L. Characterization of the high affinity heparin binding site of the Alzheimer\u2019s disease beta A4 amyloid precursor protein (APP) and its enhancement by zinc(II). Journal of molecular recognition: JMR 8, 247\u2013257, https:\/\/doi.org\/10.1002\/jmr.300080403 (1995).","journal-title":"Journal of molecular recognition: JMR"},{"key":"37476_CR32","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1046\/j.1432-1327.1999.00957.x","volume":"266","author":"J McLaurin","year":"1999","unstructured":"McLaurin, J., Franklin, T., Zhang, X., Deng, J. & Fraser, P. E. Interactions of Alzheimer amyloid-beta peptides with glycosaminoglycans effects on fibril nucleation and growth. European journal of biochemistry 266, 1101\u20131110 (1999).","journal-title":"European journal of biochemistry"},{"key":"37476_CR33","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/S0304-3940(96)13235-3","volume":"220","author":"A Matsumoto","year":"1996","unstructured":"Matsumoto, A., Enomoto, T., Fujiwara, Y., Baba, H. & Matsumoto, R. Enhanced aggregation of beta-amyloid-containing peptides by extracellular matrix and their degradation by the 68 kDa serine protease prepared from human brain. Neuroscience letters 220, 159\u2013162 (1996).","journal-title":"Neuroscience letters"},{"key":"37476_CR34","doi-asserted-by":"publisher","first-page":"1531","DOI":"10.1111\/j.1471-4159.1992.tb08470.x","volume":"59","author":"PE Fraser","year":"1992","unstructured":"Fraser, P. E., Nguyen, J. T., Chin, D. T. & Kirschner, D. A. Effects of sulfate ions on Alzheimer beta\/A4 peptide assemblies: implications for amyloid fibril-proteoglycan interactions. Journal of neurochemistry 59, 1531\u20131540 (1992).","journal-title":"Journal of neurochemistry"},{"key":"37476_CR35","doi-asserted-by":"publisher","first-page":"991","DOI":"10.3233\/JAD-160751","volume":"56","author":"R Salza","year":"2017","unstructured":"Salza, R., Lethias, C. & Ricard-Blum, S. The Multimerization State of the Amyloid-beta42 Amyloid Peptide Governs its Interaction Network with the Extracellular Matrix. Journal of Alzheimer\u2019s disease: JAD 56, 991\u20131005, https:\/\/doi.org\/10.3233\/JAD-160751 (2017).","journal-title":"Journal of Alzheimer\u2019s disease: JAD"},{"key":"37476_CR36","doi-asserted-by":"publisher","first-page":"604","DOI":"10.1007\/s004010100414","volume":"102","author":"J van Horssen","year":"2001","unstructured":"van Horssen, J. et al. Heparan sulfate proteoglycan expression in cerebrovascular amyloid beta deposits in Alzheimer\u2019s disease and hereditary cerebral hemorrhage with amyloidosis (Dutch) brains. Acta neuropathologica 102, 604\u2013614 (2001).","journal-title":"Acta neuropathologica"},{"key":"37476_CR37","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.matbio.2010.10.006","volume":"30","author":"Y Choi","year":"2011","unstructured":"Choi, Y., Chung, H., Jung, H., Couchman, J. R. & Oh, E. S. Syndecans as cell surface receptors: Unique structure equates with functional diversity. Matrix biology: journal of the International Society for Matrix Biology 30, 93\u201399, https:\/\/doi.org\/10.1016\/j.matbio.2010.10.006 (2011).","journal-title":"Matrix biology: journal of the International Society for Matrix Biology"},{"key":"37476_CR38","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1161\/01.RES.0000159708.71142.c8","volume":"96","author":"E Tkachenko","year":"2005","unstructured":"Tkachenko, E., Rhodes, J. M. & Simons, M. Syndecans: new kids on the signaling block. Circulation research 96, 488\u2013500, https:\/\/doi.org\/10.1161\/01.RES.0000159708.71142.c8 (2005).","journal-title":"Circulation research"},{"key":"37476_CR39","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/S0945-053X(03)00010-6","volume":"22","author":"A Yoneda","year":"2003","unstructured":"Yoneda, A. & Couchman, J. R. Regulation of cytoskeletal organization by syndecan transmembrane proteoglycans. Matrix biology: journal of the International Society for Matrix Biology 22, 25\u201333 (2003).","journal-title":"Matrix biology: journal of the International Society for Matrix Biology"},{"key":"37476_CR40","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1111\/febs.13940","volume":"284","author":"NA Afratis","year":"2017","unstructured":"Afratis, N. A. et al. Syndecans - key regulators of cell signaling and biological functions. The FEBS journal 284, 27\u201341, https:\/\/doi.org\/10.1111\/febs.13940 (2017).","journal-title":"The FEBS journal"},{"key":"37476_CR41","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/iep.12112","volume":"96","author":"JR Couchman","year":"2015","unstructured":"Couchman, J. R., Gopal, S., Lim, H. C., Norgaard, S. & Multhaupt, H. A. Fell-Muir Lecture: Syndecans: from peripheral coreceptors to mainstream regulators of cell behaviour. International journal of experimental pathology 96, 1\u201310, https:\/\/doi.org\/10.1111\/iep.12112 (2015).","journal-title":"International journal of experimental pathology"},{"key":"37476_CR42","doi-asserted-by":"publisher","first-page":"3863","DOI":"10.1111\/j.1742-4658.2010.07796.x","volume":"277","author":"RV Iozzo","year":"2010","unstructured":"Iozzo, R. V. & Karamanos, N. Proteoglycans in health and disease: emerging concepts and future directions. The FEBS journal 277, 3863, https:\/\/doi.org\/10.1111\/j.1742-4658.2010.07796.x (2010).","journal-title":"The FEBS journal"},{"key":"37476_CR43","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1146\/annurev.cb.08.110192.002053","volume":"8","author":"M Bernfield","year":"1992","unstructured":"Bernfield, M. et al. Biology of the syndecans: a family of transmembrane heparan sulfate proteoglycans. Annual review of cell biology 8, 365\u2013393, https:\/\/doi.org\/10.1146\/annurev.cb.08.110192.002053 (1992).","journal-title":"Annual review of cell biology"},{"key":"37476_CR44","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1146\/annurev-cellbio-100109-104126","volume":"26","author":"JR Couchman","year":"2010","unstructured":"Couchman, J. R. Transmembrane signaling proteoglycans. Annual review of cell and developmental biology 26, 89\u2013114, https:\/\/doi.org\/10.1146\/annurev-cellbio-100109-104126 (2010).","journal-title":"Annual review of cell and developmental biology"},{"key":"37476_CR45","doi-asserted-by":"crossref","first-page":"12304","DOI":"10.1016\/S0021-9258(17)32716-3","volume":"269","author":"R Kokenyesi","year":"1994","unstructured":"Kokenyesi, R. & Bernfield, M. Core protein structure and sequence determine the site and presence of heparan sulfate and chondroitin sulfate on syndecan-1. The Journal of biological chemistry 269, 12304\u201312309 (1994).","journal-title":"The Journal of biological chemistry"},{"key":"37476_CR46","doi-asserted-by":"publisher","first-page":"12901","DOI":"10.1074\/jbc.272.20.12901","volume":"272","author":"AJ McFall","year":"1997","unstructured":"McFall, A. J. & Rapraeger, A. C. Identification of an adhesion site within the syndecan-4 extracellular protein domain. The Journal of biological chemistry 272, 12901\u201312904 (1997).","journal-title":"The Journal of biological chemistry"},{"key":"37476_CR47","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.matbio.2013.10.004","volume":"35","author":"HC Christianson","year":"2014","unstructured":"Christianson, H. C. & Belting, M. Heparan sulfate proteoglycan as a cell-surface endocytosis receptor. Matrix biology: journal of the International Society for Matrix Biology 35, 51\u201355, https:\/\/doi.org\/10.1016\/j.matbio.2013.10.004 (2014).","journal-title":"Matrix biology: journal of the International Society for Matrix Biology"},{"key":"37476_CR48","doi-asserted-by":"publisher","first-page":"e5","DOI":"10.1017\/S1462399409001367","volume":"12","author":"AH Bartlett","year":"2010","unstructured":"Bartlett, A. H. & Park, P. W. Proteoglycans in host-pathogen interactions: molecular mechanisms and therapeutic implications. Expert reviews in molecular medicine 12, e5, https:\/\/doi.org\/10.1017\/S1462399409001367 (2010).","journal-title":"Expert reviews in molecular medicine"},{"key":"37476_CR49","doi-asserted-by":"publisher","first-page":"220","DOI":"10.3389\/fmicb.2016.00220","volume":"7","author":"B Garcia","year":"2016","unstructured":"Garcia, B. et al. Surface Proteoglycans as Mediators in Bacterial Pathogens Infections. Frontiers in microbiology 7, 220, https:\/\/doi.org\/10.3389\/fmicb.2016.00220 (2016).","journal-title":"Frontiers in microbiology"},{"key":"37476_CR50","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/S1016-8478(23)14017-9","volume":"26","author":"Y Chen","year":"2008","unstructured":"Chen, Y., Gotte, M., Liu, J. & Park, P. W. Microbial subversion of heparan sulfate proteoglycans. Molecules and cells 26, 415\u2013426 (2008).","journal-title":"Molecules and cells"},{"key":"37476_CR51","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1111\/j.1600-0854.2007.00540.x","volume":"8","author":"CK Payne","year":"2007","unstructured":"Payne, C. K., Jones, S. A., Chen, C. & Zhuang, X. Internalization and trafficking of cell surface proteoglycans and proteoglycan-binding ligands. Traffic 8, 389\u2013401, https:\/\/doi.org\/10.1111\/j.1600-0854.2007.00540.x (2007).","journal-title":"Traffic"},{"key":"37476_CR52","doi-asserted-by":"publisher","first-page":"44431","DOI":"10.1074\/jbc.M205241200","volume":"277","author":"F Cheng","year":"2002","unstructured":"Cheng, F. et al. Nitric oxide-dependent processing of heparan sulfate in recycling S-nitrosylated glypican-1 takes place in caveolin-1-containing endosomes. The Journal of biological chemistry 277, 44431\u201344439, https:\/\/doi.org\/10.1074\/jbc.M205241200 (2002).","journal-title":"The Journal of biological chemistry"},{"key":"37476_CR53","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1042\/BST0350788","volume":"35","author":"GM Poon","year":"2007","unstructured":"Poon, G. M. & Gariepy, J. Cell-surface proteoglycans as molecular portals for cationic peptide and polymer entry into cells. Biochemical Society transactions 35, 788\u2013793, https:\/\/doi.org\/10.1042\/BST0350788 (2007).","journal-title":"Biochemical Society transactions"},{"key":"37476_CR54","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.jconrel.2014.02.011","volume":"180","author":"ME Favretto","year":"2014","unstructured":"Favretto, M. E., Wallbrecher, R., Schmidt, S., van de Putte, R. & Brock, R. Glycosaminoglycans in the cellular uptake of drug delivery vectors - bystanders or active players? Journal of controlled release: official journal of the Controlled Release Society 180, 81\u201390, https:\/\/doi.org\/10.1016\/j.jconrel.2014.02.011 (2014).","journal-title":"Journal of controlled release: official journal of the Controlled Release Society"},{"key":"37476_CR55","doi-asserted-by":"publisher","first-page":"2142","DOI":"10.1529\/biophysj.107.113472","volume":"94","author":"A Ziegler","year":"2008","unstructured":"Ziegler, A. & Seelig, J. Binding and clustering of glycosaminoglycans: a common property of mono- and multivalent cell-penetrating compounds. Biophysical journal 94, 2142\u20132149, https:\/\/doi.org\/10.1529\/biophysj.107.113472 (2008).","journal-title":"Biophysical journal"},{"key":"37476_CR56","doi-asserted-by":"publisher","first-page":"2258","DOI":"10.1016\/j.bbamem.2010.01.022","volume":"1798","author":"T Letoha","year":"2010","unstructured":"Letoha, T. et al. Cell-penetrating peptide exploited syndecans. Biochim Biophys Acta 1798, 2258\u20132265, https:\/\/doi.org\/10.1016\/j.bbamem.2010.01.022 (2010).","journal-title":"Biochim Biophys Acta"},{"key":"37476_CR57","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1016\/j.ejps.2013.05.022","volume":"49","author":"T Letoha","year":"2013","unstructured":"Letoha, T. et al. Contribution of syndecans to lipoplex-mediated gene delivery. Eur J Pharm Sci 49, 550\u2013555, https:\/\/doi.org\/10.1016\/j.ejps.2013.05.022 (2013).","journal-title":"Eur J Pharm Sci"},{"key":"37476_CR58","doi-asserted-by":"publisher","first-page":"1479","DOI":"10.4155\/tde.13.112","volume":"4","author":"L Szilak","year":"2013","unstructured":"Szilak, L., Letoha, T. & Ughy, B. What is the potential of syndecan-4-targeted novel delivery technologies? Therapeutic delivery 4, 1479\u20131481, https:\/\/doi.org\/10.4155\/tde.13.112 (2013).","journal-title":"Therapeutic delivery"},{"key":"37476_CR59","unstructured":"Szil\u00e1k, L., Keller-Pint\u00e9r, A., T\u00edm\u00e1r, J. & Letoha, T. (Google Patents, 2014)."},{"key":"37476_CR60","doi-asserted-by":"publisher","first-page":"7415","DOI":"10.1523\/JNEUROSCI.19-17-07415.1999","volume":"19","author":"YP Hsueh","year":"1999","unstructured":"Hsueh, Y. P. & Sheng, M. Regulated expression and subcellular localization of syndecan heparan sulfate proteoglycans and the syndecan-binding protein CASK\/LIN-2 during rat brain development. The Journal of neuroscience: the official journal of the Society for Neuroscience 19, 7415\u20137425 (1999).","journal-title":"The Journal of neuroscience: the official journal of the Society for Neuroscience"},{"key":"37476_CR61","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/0167-4889(94)90026-4","volume":"1222","author":"L Attisano","year":"1994","unstructured":"Attisano, L., Wrana, J. L., Lopez-Casillas, F. & Massague, J. TGF-beta receptors and actions. Biochim Biophys Acta 1222, 71\u201380 (1994).","journal-title":"Biochim Biophys Acta"},{"key":"37476_CR62","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1016\/S1525-0016(03)00042-X","volume":"7","author":"W Shi","year":"2003","unstructured":"Shi, W. & Bartlett, J. S. RGD inclusion in VP3 provides adeno-associated virus type 2 (AAV2)-based vectors with a heparan sulfate-independent cell entry mechanism. Molecular therapy: the journal of the American Society of Gene Therapy 7, 515\u2013525 (2003).","journal-title":"Molecular therapy: the journal of the American Society of Gene Therapy"},{"key":"37476_CR63","doi-asserted-by":"publisher","first-page":"13125","DOI":"10.1128\/JVI.77.24.13125-13135.2003","volume":"77","author":"S Shafti-Keramat","year":"2003","unstructured":"Shafti-Keramat, S. et al. Different heparan sulfate proteoglycans serve as cellular receptors for human papillomaviruses. Journal of virology 77, 13125\u201313135 (2003).","journal-title":"Journal of virology"},{"key":"37476_CR64","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1083\/jcb.133.2.405","volume":"133","author":"R Steinfeld","year":"1996","unstructured":"Steinfeld, R., Van Den Berghe, H. & David, G. Stimulation of fibroblast growth factor receptor-1 occupancy and signaling by cell surface-associated syndecans and glypican. The Journal of cell biology 133, 405\u2013416 (1996).","journal-title":"The Journal of cell biology"},{"key":"37476_CR65","doi-asserted-by":"publisher","first-page":"9187","DOI":"10.1128\/JVI.75.19.9187-9200.2001","volume":"75","author":"AC Saphire","year":"2001","unstructured":"Saphire, A. C., Bobardt, M. D., Zhang, Z., David, G. & Gallay, P. A. Syndecans serve as attachment receptors for human immunodeficiency virus type 1 on macrophages. Journal of virology 75, 9187\u20139200, https:\/\/doi.org\/10.1128\/JVI.75.19.9187-9200.2001 (2001).","journal-title":"Journal of virology"},{"key":"37476_CR66","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1002\/cyto.a.20014","volume":"58","author":"S Busetto","year":"2004","unstructured":"Busetto, S., Trevisan, E., Patriarca, P. & Menegazzi, R. A single-step, sensitive flow cytofluorometric assay for the simultaneous assessment of membrane-bound and ingested Candida albicans in phagocytosing neutrophils. Cytometry. Part A: the journal of the International Society for Analytical Cytology 58, 201\u2013206, https:\/\/doi.org\/10.1002\/cyto.a.20014 (2004).","journal-title":"Cytometry. Part A: the journal of the International Society for Analytical Cytology"},{"key":"37476_CR67","doi-asserted-by":"publisher","first-page":"2510","DOI":"10.3390\/molecules20022510","volume":"20","author":"C Iannuzzi","year":"2015","unstructured":"Iannuzzi, C., Irace, G. & Sirangelo, I. The effect of glycosaminoglycans (GAGs) on amyloid aggregation and toxicity. Molecules 20, 2510\u20132528, https:\/\/doi.org\/10.3390\/molecules20022510 (2015).","journal-title":"Molecules"},{"key":"37476_CR68","doi-asserted-by":"publisher","first-page":"12806","DOI":"10.1021\/bi0610653","volume":"45","author":"M Calamai","year":"2006","unstructured":"Calamai, M. et al. Nature and significance of the interactions between amyloid fibrils and biological polyelectrolytes. Biochemistry 45, 12806\u201312815, https:\/\/doi.org\/10.1021\/bi0610653 (2006).","journal-title":"Biochemistry"},{"key":"37476_CR69","doi-asserted-by":"publisher","first-page":"3933","DOI":"10.1242\/jcs.092015","volume":"124","author":"GP Otto","year":"2011","unstructured":"Otto, G. P. & Nichols, B. J. The roles of flotillin microdomains\u2013endocytosis and beyond. Journal of cell science 124, 3933\u20133940, https:\/\/doi.org\/10.1242\/jcs.092015 (2011).","journal-title":"Journal of cell science"},{"key":"37476_CR70","doi-asserted-by":"publisher","first-page":"36267","DOI":"10.1074\/jbc.274.51.36267","volume":"274","author":"F Safaiyan","year":"1999","unstructured":"Safaiyan, F. et al. Selective effects of sodium chlorate treatment on the sulfation of heparan sulfate. The Journal of biological chemistry 274, 36267\u201336273 (1999).","journal-title":"The Journal of biological chemistry"},{"key":"37476_CR71","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1099\/jmm.0.05497-0","volume":"53","author":"S Fadel","year":"2004","unstructured":"Fadel, S. & Eley, A. Chlorate: a reversible inhibitor of proteoglycan sulphation in Chlamydia trachomatis-infected cells. Journal of medical microbiology 53, 93\u201395, https:\/\/doi.org\/10.1099\/jmm.0.05497-0 (2004).","journal-title":"Journal of medical microbiology"},{"key":"37476_CR72","doi-asserted-by":"publisher","first-page":"595","DOI":"10.15252\/emmm.201606210","volume":"8","author":"DJ Selkoe","year":"2016","unstructured":"Selkoe, D. J. & Hardy, J. The amyloid hypothesis of Alzheimer\u2019s disease at 25 years. EMBO molecular medicine 8, 595\u2013608, https:\/\/doi.org\/10.15252\/emmm.201606210 (2016).","journal-title":"EMBO molecular medicine"},{"key":"37476_CR73","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1111\/j.1471-4159.2004.02737.x","volume":"91","author":"O Wirths","year":"2004","unstructured":"Wirths, O., Multhaup, G. & Bayer, T. A. A modified beta-amyloid hypothesis: intraneuronal accumulation of the beta-amyloid peptide\u2013the first step of a fatal cascade. Journal of neurochemistry 91, 513\u2013520, https:\/\/doi.org\/10.1111\/j.1471-4159.2004.02737.x (2004).","journal-title":"Journal of neurochemistry"},{"key":"37476_CR74","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1111\/pin.12520","volume":"67","author":"RH Takahashi","year":"2017","unstructured":"Takahashi, R. H., Nagao, T. & Gouras, G. K. Plaque formation and the intraneuronal accumulation of beta-amyloid in Alzheimer\u2019s disease. Pathology international 67, 185\u2013193, https:\/\/doi.org\/10.1111\/pin.12520 (2017).","journal-title":"Pathology international"},{"key":"37476_CR75","doi-asserted-by":"publisher","first-page":"277","DOI":"10.3389\/fphys.2015.00277","volume":"6","author":"R Zeineddine","year":"2015","unstructured":"Zeineddine, R. & Yerbury, J. J. The role of macropinocytosis in the propagation of protein aggregation associated with neurodegenerative diseases. Frontiers in physiology 6, 277, https:\/\/doi.org\/10.3389\/fphys.2015.00277 (2015).","journal-title":"Frontiers in physiology"},{"key":"37476_CR76","doi-asserted-by":"publisher","first-page":"e99939","DOI":"10.1371\/journal.pone.0099939","volume":"9","author":"Y Li","year":"2014","unstructured":"Li, Y. et al. Mechanisms of U87 astrocytoma cell uptake and trafficking of monomeric versus protofibril Alzheimer's disease amyloid-beta proteins. Plos one 9, e99939, https:\/\/doi.org\/10.1371\/journal.pone.0099939 (2014).","journal-title":"Plos one"},{"key":"37476_CR77","doi-asserted-by":"publisher","first-page":"4252","DOI":"10.1523\/JNEUROSCI.5572-08.2009","volume":"29","author":"S Mandrekar","year":"2009","unstructured":"Mandrekar, S. et al. Microglia mediate the clearance of soluble Abeta through fluid phase macropinocytosis. The Journal of neuroscience: the official journal of the Society for Neuroscience 29, 4252\u20134262, https:\/\/doi.org\/10.1523\/JNEUROSCI.5572-08.2009 (2009).","journal-title":"The Journal of neuroscience: the official journal of the Society for Neuroscience"},{"key":"37476_CR78","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1021\/bi0612824","volume":"46","author":"I Nakase","year":"2007","unstructured":"Nakase, I. et al. Interaction of arginine-rich peptides with membrane-associated proteoglycans is crucial for induction of actin organization and macropinocytosis. Biochemistry 46, 492\u2013501, https:\/\/doi.org\/10.1021\/bi0612824 (2007).","journal-title":"Biochemistry"},{"key":"37476_CR79","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1083\/jcb.200911091","volume":"189","author":"NC Hubner","year":"2010","unstructured":"Hubner, N. C. et al. Quantitative proteomics combined with BAC TransgeneOmics reveals in vivo protein interactions. The Journal of cell biology 189, 739\u2013754, https:\/\/doi.org\/10.1083\/jcb.200911091 (2010).","journal-title":"The Journal of cell biology"},{"key":"37476_CR80","doi-asserted-by":"publisher","first-page":"1992","DOI":"10.15252\/embj.201490899","volume":"34","author":"K Kobayashi","year":"2015","unstructured":"Kobayashi, K. et al. Transcriptional repression by MYB3R proteins regulates plant organ growth. The EMBO journal 34, 1992\u20132007, https:\/\/doi.org\/10.15252\/embj.201490899 (2015).","journal-title":"The EMBO journal"},{"key":"37476_CR81","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.15252\/embj.201694561","volume":"36","author":"BM Horvath","year":"2017","unstructured":"Horvath, B. M. et al. Arabidopsis Retinoblastoma Related directly regulates DNA damage responses through functions beyond cell cycle control. The EMBO journal 36, 1261\u20131278, https:\/\/doi.org\/10.15252\/embj.201694561 (2017).","journal-title":"The EMBO journal"},{"key":"37476_CR82","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.brainres.2016.02.047","volume":"1647","author":"Y Li","year":"2016","unstructured":"Li, Y. et al. Immunoprecipitation and mass spectrometry defines an extensive RBM45 protein-protein interaction network. Brain research 1647, 79\u201393, https:\/\/doi.org\/10.1016\/j.brainres.2016.02.047 (2016).","journal-title":"Brain research"},{"key":"37476_CR83","doi-asserted-by":"publisher","first-page":"160696","DOI":"10.1098\/rsos.160696","volume":"4","author":"C Xue","year":"2017","unstructured":"Xue, C., Lin, T. Y., Chang, D. & Guo, Z. Thioflavin T as an amyloid dye: fibril quantification, optimal concentration and effect on aggregation. Royal Society open science 4, 160696, https:\/\/doi.org\/10.1098\/rsos.160696 (2017).","journal-title":"Royal Society open science"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-37476-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-37476-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-37476-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,14]],"date-time":"2024-07-14T14:39:54Z","timestamp":1720967994000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-37476-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2,4]]},"references-count":83,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["37476"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-37476-9","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,2,4]]},"assertion":[{"value":"14 August 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 December 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 February 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"1393"}}