{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T06:40:25Z","timestamp":1782801625602,"version":"3.54.5"},"reference-count":39,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,9,27]],"date-time":"2020-09-27T00:00:00Z","timestamp":1601164800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19K11781"],"award-info":[{"award-number":["19K11781"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Nutritional factors can affect the risk of developing neurological disorders and their rate of progression. In particular, abnormalities of carbohydrate metabolism in diabetes mellitus patients lead to an increased risk of neurological disorders such as Alzheimer\u2019s disease (AD). In this study, we investigated the relationship between nervous system disorder and the pathogenesis of AD by exposing SH-SY5Y neuroblastoma cells to glyceraldehyde (GA). We previously reported that GA-derived toxic advanced glycation end products (toxic AGEs, TAGE) induce AD-like alterations including intracellular tau phosphorylation. However, the role of TAGE and their target molecules in the pathogenesis of AD remains unclear. In this study, we investigated the target protein for TAGE by performing two-dimensional immunoblot analysis with anti-TAGE antibody and mass spectrometry and identified \u03b2-tubulin as one of the targets. GA treatment induced TAGE-\u03b2-tubulin formation and abnormal aggregation of \u03b2-tubulin, and inhibited neurite outgrowth in SH-SY5Y cells. On the other hand, glucose-derived AGEs were also involved in developing AD. However, glucose did not make abnormal aggregation of \u03b2-tubulin and did not inhibit neurite outgrowth. Understanding the underlying mechanism of TAGE-\u03b2-tubulin formation by GA and its role in neurodegeneration may aid in the development of novel therapeutics and neuroprotection strategies.<\/jats:p>","DOI":"10.3390\/nu12102958","type":"journal-article","created":{"date-parts":[[2020,9,27]],"date-time":"2020-09-27T22:24:42Z","timestamp":1601245482000},"page":"2958","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["The Effect of Glyceraldehyde-Derived Advanced Glycation End Products on \u03b2-Tubulin-Inhibited Neurite Outgrowth in SH-SY5Y Human Neuroblastoma Cells"],"prefix":"10.3390","volume":"12","author":[{"given":"Ryuto","family":"Nasu","sequence":"first","affiliation":[{"name":"Graduate School and Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3 Minamitamagaki, Suzuka 513-8670, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayako","family":"Furukawa","sequence":"additional","affiliation":[{"name":"Graduate School and Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3 Minamitamagaki, Suzuka 513-8670, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keita","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Graduate School and Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3 Minamitamagaki, Suzuka 513-8670, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1057-3764","authenticated-orcid":false,"given":"Masayoshi","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada-machi, Ishikawa 920-0293, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8777-329X","authenticated-orcid":false,"given":"Yoshiki","family":"Koriyama","sequence":"additional","affiliation":[{"name":"Graduate School and Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3 Minamitamagaki, Suzuka 513-8670, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1177\/1533317506289277","article-title":"Toxic advanced glycation end products (TAGE) theory in Alzheimer\u2019s disease","volume":"21","author":"Sato","year":"2006","journal-title":"Am. J. Alzheimers Dis. Other Demen."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"305","DOI":"10.2174\/1566524013363735","article-title":"Alternative routes for the formation of immunochemically distinct advanced glycation end-products in vivo","volume":"1","author":"Takeuchi","year":"2001","journal-title":"Curr. Mol. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.mehy.2004.02.042","article-title":"TAGE (toxic AGEs) hypothesis in various chronic diseases","volume":"63","author":"Takeuchi","year":"2004","journal-title":"Med. Hypotheses."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.2174\/1389450111009011468","article-title":"Involvement of the toxic AGEs (TAGE)-RAGE system in the pathogenesis of diabetic vascular complications: A novel therapeutic strategy","volume":"11","author":"Takeuchi","year":"2010","journal-title":"Curr. Drug Targets"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5710","DOI":"10.1073\/pnas.91.12.5710","article-title":"Advanced maillard reaction end products are associated with Alzheimer disease pathology","volume":"91","author":"Smith","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/nm0795-693","article-title":"Non-enzymatically glycated tau in Alzheimer\u2019s disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid beta-peptide","volume":"1","author":"Yan","year":"1995","journal-title":"Nat. Med."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Takeuchi, M. (2016). Serum Levels of toxic AGEs (TAGE) may be a promising novel biomarker for the onset\/progression of lifestyle-related diseases. Diagnostics (Basel), 6.","DOI":"10.3390\/diagnostics6020023"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1093\/jnen\/59.12.1094","article-title":"Neurotoxicity of advanced glycation end-products for cultured cortical neurons","volume":"59","author":"Takeuchi","year":"2000","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"13313","DOI":"10.1038\/srep13313","article-title":"Glyceraldehyde caused Alzheimer\u2019s disease-like alterations in diagnostic marker levels in SH-SY5Y human neuroblastoma cells","volume":"5","author":"Koriyama","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2121","DOI":"10.1038\/s41598-019-39202-5","article-title":"Intracellular toxic advanced glycation end-products in cardiomyocytes may cause cardiovascular disease","volume":"9","author":"Takata","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.3748\/wjg.v21.i6.1784","article-title":"In vitro identification of nonalcoholic fatty liver disease-related protein hnRNPM","volume":"21","author":"Takino","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1146\/annurev.neuro.24.1.1121","article-title":"Neurodegenerative tauopathies","volume":"24","author":"Lee","year":"2001","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/0092-8674(86)90318-1","article-title":"Beyond self-assembly: From microtubules to morphogenesis","volume":"45","author":"Kirschner","year":"1986","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s00401-004-0871-x","article-title":"Glyceraldehyde-derived advanced glycation end products in Alzheimer\u2019s disease","volume":"108","author":"Choei","year":"2004","journal-title":"Acta. Neuropathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/S0014-2999(02)02789-9","article-title":"Propentofylline protects beta-amyloid protein-induced apoptosis in cultured rat hippocampal neurons","volume":"458","author":"Koriyama","year":"2003","journal-title":"Eur. J. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1007\/BF03401779","article-title":"Immunological evidence that non-carboxymethyllysine advanced glycation end-products are produced from short chain sugars and dicarbonyl compounds in vivo","volume":"6","author":"Takeuchi","year":"2000","journal-title":"Mol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2618","DOI":"10.2337\/dc12-0087","article-title":"Positive association between serum level of glyceraldehyde-derived advanced glycation end products and vascular inflammation evaluated by [(18)F] fluorodeoxyglucose positron emission tomography","volume":"35","author":"Tahara","year":"2012","journal-title":"Diabetes Care"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1016\/j.nbd.2011.05.024","article-title":"Proteomic identification of hippocampal proteins vulnerable to oxidative stress in excitotoxin-induced acute neuronal injury","volume":"43","author":"Furukawa","year":"2011","journal-title":"Neurobiol. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"26503","DOI":"10.1074\/jbc.274.37.26503","article-title":"Specific activation of the p38 mitogen-activated protein kinase signaling pathway and induction of neurite outgrowth in PC12 cells by bone morphogenetic protein-2","volume":"274","author":"Iwasaki","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"10006","DOI":"10.1523\/JNEUROSCI.2580-06.2006","article-title":"Alpha-internexin is structurally and functionally associated with the neurofilament triplet proteins in the mature CNS","volume":"26","author":"Yuan","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1937","DOI":"10.1212\/WNL.53.9.1937","article-title":"Diabetes mellitus and the risk of dementia: The Rotterdam Study","volume":"53","author":"Ott","year":"1999","journal-title":"Neurology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/S0165-6147(02)02037-0","article-title":"Does insulin dysfunction play a role in Alzheimer\u2019s disease?","volume":"23","author":"Gasparini","year":"2002","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"27","DOI":"10.2165\/00023210-200317010-00003","article-title":"The role of insulin resistance in the pathogenesis of Alzheimer\u2019s disease: Implications for treatment","volume":"17","author":"Watson","year":"2003","journal-title":"CNS Drugs"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1038\/382685a0","article-title":"RAGE and amyloid-beta peptide neurotoxicity in Alzheimer\u2019s disease","volume":"382","author":"Yan","year":"1996","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4766","DOI":"10.1073\/pnas.91.11.4766","article-title":"Advanced glycation end products contribute to amyloidosis in Alzheimer disease","volume":"91","author":"Vitek","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1097\/01.WCB.0000090622.86921.0E","article-title":"Advanced glycation endproducts induce changes in glucose consumption, lactate production, and ATP levels in SH-SY5Y neuroblastoma cells by a redox-sensitive mechanism","volume":"23","author":"Arriba","year":"2003","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1007\/s00702-003-0038-2","article-title":"Differential effects of \u201cadvanced glycation endproducts\u201dand beta-amyloid peptide on glucose utilization and ATP levels in the neuronal cell line SH-SY5Y","volume":"111","author":"Kuhla","year":"2004","journal-title":"J. Neural Transm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/BF03402128","article-title":"Detection of noncarboxymethyllysine and carboxymethyllysine advanced glycation end products (AGE) in serum of diabetic patients","volume":"5","author":"Takeuchi","year":"1999","journal-title":"Mol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"39","DOI":"10.2174\/1567205043480582","article-title":"Involvement of advanced glycation end-products (AGEs) in Alzheimer\u2019s disease","volume":"1","author":"Takeuchi","year":"2004","journal-title":"Curr. Alzheimer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1007\/BF00403175","article-title":"Glycation of rat sciatic nerve tubulin in experimental diabetes mellitus","volume":"34","author":"Cullum","year":"1991","journal-title":"Diabetologia"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"973","DOI":"10.2174\/138161208784139693","article-title":"Possible involvement of advanced glycation end-products (AGEs) in the pathogenesis of Alzheimer\u2019s disease","volume":"14","author":"Takeuchi","year":"2008","journal-title":"Curr. Pharm. Des."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/S0074-7742(02)50082-9","article-title":"Polyol pathway and diabetic peripheral neuropathy","volume":"50","author":"Oates","year":"2002","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2652","DOI":"10.1096\/fasebj.4.9.2189777","article-title":"Metabolic effects of dietary fructose","volume":"4","author":"Hallfrisch","year":"1990","journal-title":"FASEB J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1111\/jnc.13079","article-title":"Uptake and metabolism of fructose by rat neocortical cells in vivo and by isolated nerve terminals in vitro","volume":"133","author":"Hassel","year":"2015","journal-title":"J. Neurochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1042\/bj2300053","article-title":"The purification and properties of human liver ketohexokinase. A role for ketohexokinase and fructose-bisphosphate aldolase in the metabolic production of oxalate from xylitol","volume":"230","author":"Bais","year":"1985","journal-title":"Biochem. J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1093\/oxfordjournals.jbchem.a135662","article-title":"Phosphorylated tau protein is integrated into paired helical filaments in Alzheimer\u2019s disease","volume":"99","author":"Ihara","year":"1986","journal-title":"J. Biochem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5646","DOI":"10.1073\/pnas.86.14.5646","article-title":"Identification and localization of a tau peptide to paired helical filaments of Alzheimer disease","volume":"86","author":"Iqbal","year":"1989","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1046\/j.1471-4159.1995.65041658.x","article-title":"Tau protein from Alzheimer\u2019s disease patients is glycated at its tubulin-binding domain","volume":"65","author":"Ledesma","year":"1995","journal-title":"J. Neurochem."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Ando, K., Otake, A.M., Ohtake, Y., Hayashishita, M., Sekiya, M., and Iijima, K.M. (2016). Stabilization of microtubule-unbound tau via tau phosphorylation at Ser262\/356 by Par-1\/MARK contributes to augmentation of AD-related phosphorylation and A\u03b242-induced tau toxicity. PLoS Genet., 12.","DOI":"10.1371\/journal.pgen.1005917"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/10\/2958\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:14:12Z","timestamp":1760177652000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/10\/2958"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,27]]},"references-count":39,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2020,10]]}},"alternative-id":["nu12102958"],"URL":"https:\/\/doi.org\/10.3390\/nu12102958","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,27]]}}}