{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:47:15Z","timestamp":1792784835798,"version":"4.5.0"},"reference-count":66,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81872853"],"award-info":[{"award-number":["81872853"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31970968"],"award-info":[{"award-number":["31970968"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the science and technology project of nantong city"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Psychiatry"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Gangliosides serve as receptors for proteins, bacteria, and viruses, with sialylation at the termini of their glycan chains playing a crucial role in ligand recognition and endocytosis. The internalization of proteopathic tau aggregates by neurons is integral to the propagation of tau pathology in Alzheimer\u2019s disease (AD). However, the influence of gangliosides and their sialylation modifications on the uptake of proteopathic tau aggregates and the subsequent impact on AD pathology remains unclear. This study investigates the roles of the four mammalian sialidases (Neu1-Neu4) in modulating tau aggregation in cellular models. Our findings demonstrate that Neu3 significantly inhibits tau aggregation induced by proteopathic tau derived from the brains of AD patients (AD P-tau). Overexpressing Neu3 or administering ganglioside GM1, which results from Neu3-catalyzed removal of one sialic acid from GD1a, in the mouse model decreases the GD1a\/GM1 ratio in mouse brain, effectively blocks the spread of tau pathology and improves recognition in AD P-tau-injected mice. Both Neu3 and GM1 reduce the internalization of tau aggregates, while GD1a enhances tau uptake, showing a positive correlation with the level of internalized tau. Moreover, the internalization of tau mediated by GD1a dependent on low-density lipoprotein receptor-related protein 1 (LRP1) and compensates for heparin-inhibited tau uptake. In vitro assays demonstrate that GD1a exhibits a higher binding avidity for tau filaments than GM1. These findings indicate that GD1a may directly bind to tau aggregates via the sialic acid moiety, facilitating LRP1-mediated tau uptake. This study proposes a novel mechanism for tau internalization and posits that reducing ganglioside sialylation may be a promising strategy for hindering the spread of tau pathology in AD.<\/jats:p>","DOI":"10.1038\/s41380-025-03394-2","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T14:54:44Z","timestamp":1765810484000},"page":"2561-2574","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Ganglioside sialylation modulates tau internalization and pathology spread"],"prefix":"10.1038","volume":"31","author":[{"given":"Shiying","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianling","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruozhen","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyue","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leyi","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longfei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanli","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7277-916X","authenticated-orcid":false,"given":"Jianlan","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Miao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-hua","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8601-4419","authenticated-orcid":false,"given":"Fei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5661-9051","authenticated-orcid":false,"given":"Dandan","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,15]]},"reference":[{"key":"3394_CR1","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/S1474-4422(19)30290-X","volume":"19","author":"L Jia","year":"2020","unstructured":"Jia L, Quan M, Fu Y, Zhao T, Li Y, Wei C, et al. Dementia in China: epidemiology, clinical management, and research advances. Lancet Neurol. 2020;19:81\u201392.","journal-title":"Lancet Neurol"},{"key":"3394_CR2","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1038\/s41582-024-00989-1","volume":"20","author":"MM Mielke","year":"2024","unstructured":"Mielke MM, Fowler NR. Alzheimer disease blood biomarkers: considerations for population-level use. Nat Rev Neurol. 2024;20:495\u2013504.","journal-title":"Nat Rev Neurol"},{"key":"3394_CR3","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1038\/s41586-024-07680-x","volume":"631","author":"MAG Gilbert","year":"2024","unstructured":"Gilbert MAG, Fatima N, Jenkins J, O\u2019Sullivan TJ, Schertel A, Halfon Y, et al. CryoET of beta-amyloid and tau within postmortem Alzheimer\u2019s disease brain. Nature. 2024;631:913\u20139.","journal-title":"Nature"},{"key":"3394_CR4","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2024.116233","volume":"224","author":"D Chu","year":"2024","unstructured":"Chu D, Lei L, Gu S, Liu F, Wu F. Dual-specificity tyrosine phosphorylation-regulated kinase 1A promotes the inclusion of amyloid precursor protein exon 7. Biochem Pharmacol. 2024;224:116233.","journal-title":"Biochem Pharmacol"},{"key":"3394_CR5","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1007\/BF00688184","volume":"74","author":"I Alafuzoff","year":"1987","unstructured":"Alafuzoff I, Iqbal K, Friden H, Adolfsson R, Winblad B. Histopathological criteria for progressive dementia disorders: clinical-pathological correlation and classification by multivariate data analysis. Acta Neuropathol. 1987;74:209\u201325.","journal-title":"Acta Neuropathol"},{"key":"3394_CR6","doi-asserted-by":"publisher","first-page":"1681","DOI":"10.1212\/WNL.42.9.1681","volume":"42","author":"PV Arriagada","year":"1992","unstructured":"Arriagada PV, Marzloff K, Hyman BT. Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer\u2019s disease. Neurology. 1992;42:1681\u20138.","journal-title":"Neurology"},{"key":"3394_CR7","doi-asserted-by":"publisher","first-page":"1267","DOI":"10.1038\/s41593-023-01356-x","volume":"26","author":"A Cain","year":"2023","unstructured":"Cain A, Taga M, McCabe C, Green GS, Hekselman I, White CC, et al. Multicellular communities are perturbed in the aging human brain and Alzheimer\u2019s disease. Nat Neurosci. 2023;26:1267\u201380.","journal-title":"Nat Neurosci"},{"key":"3394_CR8","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1016\/j.jalz.2016.01.014","volume":"12","author":"W Hu","year":"2016","unstructured":"Hu W, Zhang X, Tung YC, Xie S, Liu F, Iqbal K. Hyperphosphorylation determines both the spread and the morphology of tau pathology. Alzheimers Dement. 2016;12:1066\u201377.","journal-title":"Alzheimers Dement"},{"key":"3394_CR9","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1186\/s40478-017-0488-7","volume":"5","author":"A Mudher","year":"2017","unstructured":"Mudher A, Colin M, Dujardin S, Medina M, Dewachter I, Alavi Naini SM, et al. What is the evidence that tau pathology spreads through prion-like propagation? Acta Neuropathol Commun. 2017;5:99.","journal-title":"Acta Neuropathol Commun"},{"key":"3394_CR10","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/s40478-021-01127-4","volume":"9","author":"L Li","year":"2021","unstructured":"Li L, Shi R, Gu J, Tung YC, Zhou Y, Zhou D, et al. Alzheimer\u2019s disease brain contains tau fractions with differential prion-like activities. Acta Neuropathol Commun. 2021;9:28.","journal-title":"Acta Neuropathol Commun"},{"key":"3394_CR11","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1001\/jamaneurol.2018.2505","volume":"76","author":"GS Gibbons","year":"2019","unstructured":"Gibbons GS, Lee VMY, Trojanowski JQ. Mechanisms of cell-to-cell transmission of pathological tau: a review. Jama Neurol. 2019;76:101\u20138.","journal-title":"Jama Neurol"},{"key":"3394_CR12","doi-asserted-by":"publisher","first-page":"E3138","DOI":"10.1073\/pnas.1301440110","volume":"110","author":"BB Holmes","year":"2013","unstructured":"Holmes BB, DeVos SL, Kfoury N, Li M, Jacks R, Yanamandra K, et al. Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc Natl Acad Sci USA. 2013;110:E3138\u20133147.","journal-title":"Proc Natl Acad Sci USA"},{"key":"3394_CR13","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1038\/s41586-020-2156-5","volume":"580","author":"JN Rauch","year":"2020","unstructured":"Rauch JN, Luna G, Guzman E, Audouard M, Challis C, Sibih YE, et al. LRP1 is a master regulator of tau uptake and spread. Nature. 2020;580:381\u20135.","journal-title":"Nature"},{"key":"3394_CR14","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2021.101272","volume":"67","author":"J Zhao","year":"2021","unstructured":"Zhao J, Wu H, Tang XQ. Tau internalization: A complex step in tau propagation. Ageing Res Rev. 2021;67:101272.","journal-title":"Ageing Res Rev"},{"key":"3394_CR15","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1146\/annurev-biochem-061516-045049","volume":"88","author":"J Vaquer-Alicea","year":"2019","unstructured":"Vaquer-Alicea J, Diamond MI. Propagation of protein aggregation in neurodegenerative diseases. Annu Rev Biochem. 2019;88:785\u2013810.","journal-title":"Annu Rev Biochem"},{"key":"3394_CR16","doi-asserted-by":"publisher","first-page":"2974","DOI":"10.1074\/jbc.RA119.010353","volume":"295","author":"BE Stopschinski","year":"2020","unstructured":"Stopschinski BE, Thomas TL, Nadji S, Darvish E, Fan L, Holmes BB, et al. A synthetic heparinoid blocks Tau aggregate cell uptake and amplification. J Biol Chem. 2020;295:2974\u201383.","journal-title":"J Biol Chem"},{"key":"3394_CR17","doi-asserted-by":"crossref","unstructured":"Readhead B, Klang E, Gisladottir U, Vandromme M, Li L, Quiroz YT, et al. Heparin treatment is associated with a delayed diagnosis of Alzheimer\u2019s dementia in electronic health records from two large United States health systems. Mol Psychiatr. 2024.","DOI":"10.1038\/s41380-024-02757-5"},{"key":"3394_CR18","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1007\/978-3-031-12390-0_13","volume":"29","author":"R Ledeen","year":"2023","unstructured":"Ledeen R, Chowdhury S. Gangliosides in Neurodegenerative Diseases. Adv Neurobiol. 2023;29:391\u2013418.","journal-title":"Adv Neurobiol"},{"key":"3394_CR19","doi-asserted-by":"publisher","first-page":"1802","DOI":"10.1046\/j.1471-4159.1994.63051802.x","volume":"63","author":"L Svennerholm","year":"1994","unstructured":"Svennerholm L, Bostrom K, Jungbjer B, Olsson L. Membrane lipids of adult human brain: lipid composition of frontal and temporal lobe in subjects of age 20 to 100 years. J Neurochem. 1994;63:1802\u201311.","journal-title":"J Neurochem"},{"key":"3394_CR20","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1176\/ajp.151.1.126","volume":"151","author":"C Flicker","year":"1994","unstructured":"Flicker C, Ferris SH, Kalkstein D, Serby M. A double-blind, placebo-controlled crossover study of ganglioside GM1 treatment for Alzheimer\u2019s disease. Am J Psychiatry. 1994;151:126\u20139.","journal-title":"Am J Psychiatry"},{"key":"3394_CR21","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1159\/000063604","volume":"14","author":"L Svennerholm","year":"2002","unstructured":"Svennerholm L, Brane G, Karlsson I, Lekman A, Ramstrom I, Wikkelso C. Alzheimer disease - effect of continuous intracerebroventricular treatment with GM1 ganglioside and a systematic activation programme. Dement Geriatr Cogn Disord. 2002;14:128\u201336.","journal-title":"Dement Geriatr Cogn Disord"},{"key":"3394_CR22","doi-asserted-by":"publisher","first-page":"e2106210118","DOI":"10.1073\/pnas.2106210118","volume":"118","author":"H Fatafta","year":"2021","unstructured":"Fatafta H, Khaled M, Owen MC, Sayyed-Ahmad A, Strodel B. Amyloid-beta peptide dimers undergo a random coil to beta-sheet transition in the aqueous phase but not at the neuronal membrane. Proc Natl Acad Sci USA. 2021;118:e2106210118.","journal-title":"Proc Natl Acad Sci USA"},{"key":"3394_CR23","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202303411","volume":"10","author":"X Wang","year":"2023","unstructured":"Wang X, Zhou R, Sun X, Li J, Wang J, Yue W, et al. Preferential Regulation of Gamma-Secretase-Mediated Cleavage of APP by Ganglioside GM1 Reveals a Potential Therapeutic Target for Alzheimer\u2019s Disease. Adv Sci (Weinh). 2023;10:e2303411.","journal-title":"Adv Sci (Weinh)"},{"key":"3394_CR24","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1016\/j.brainresbull.2021.05.009","volume":"173","author":"K Yang","year":"2021","unstructured":"Yang K, Yang Z, Chen X, Li W. The significance of sialylation on the pathogenesis of Alzheimer\u2019s disease. Brain Res Bull. 2021;173:116\u201323.","journal-title":"Brain Res Bull"},{"key":"3394_CR25","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1002\/med.21407","volume":"37","author":"R Szabo","year":"2017","unstructured":"Szabo R, Skropeta D. Advancement of sialyltransferase inhibitors: therapeutic challenges and opportunities. Med Res Rev. 2017;37:219\u201370.","journal-title":"Med Res Rev"},{"key":"3394_CR26","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1038\/nm.2267","volume":"17","author":"EC Nilsson","year":"2011","unstructured":"Nilsson EC, Storm RJ, Bauer J, Johansson SM, Lookene A, Angstrom J, et al. The GD1a glycan is a cellular receptor for adenoviruses causing epidemic keratoconjunctivitis. Nat Med. 2011;17:105\u20139.","journal-title":"Nat Med"},{"key":"3394_CR27","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.112114","volume":"42","author":"MN Sorin","year":"2023","unstructured":"Sorin MN, Di Maio A, Silva LM, Ebert D, Delannoy CP, Nguyen NK, et al. Structural and functional analysis of natural capsid variants suggests sialic acid-independent entry of BK polyomavirus. Cell Rep. 2023;42:112114.","journal-title":"Cell Rep"},{"key":"3394_CR28","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1038\/s41564-020-0727-8","volume":"5","author":"A Das","year":"2020","unstructured":"Das A, Barrientos R, Shiota T, Madigan V, Misumi I, McKnight KL, et al. Gangliosides are essential endosomal receptors for quasi-enveloped and naked hepatitis A virus. Nat Microbiol. 2020;5:1069\u201378.","journal-title":"Nat Microbiol"},{"key":"3394_CR29","doi-asserted-by":"publisher","first-page":"14978","DOI":"10.1073\/pnas.2001119117","volume":"117","author":"AM Kabbani","year":"2020","unstructured":"Kabbani AM, Raghunathan K, Lencer WI, Kenworthy AK, Kelly CV. Structured clustering of the glycosphingolipid GM1 is required for membrane curvature induced by cholera toxin. Proc Natl Acad Sci USA. 2020;117:14978\u201386.","journal-title":"Proc Natl Acad Sci USA"},{"key":"3394_CR30","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1093\/glycob\/cws057","volume":"22","author":"T Miyagi","year":"2012","unstructured":"Miyagi T, Yamaguchi K. Mammalian sialidases: physiological and pathological roles in cellular functions. Glycobiology. 2012;22:880\u201396.","journal-title":"Glycobiology"},{"key":"3394_CR31","doi-asserted-by":"publisher","first-page":"2477","DOI":"10.1523\/JNEUROSCI.4432-13.2014","volume":"34","author":"S Kappagantula","year":"2014","unstructured":"Kappagantula S, Andrews MR, Cheah M, Abad-Rodriguez J, Dotti CG, Fawcett JW. Neu3 sialidase-mediated ganglioside conversion is necessary for axon regeneration and is blocked in CNS axons. J Neurosci. 2014;34:2477\u201392.","journal-title":"J Neurosci"},{"key":"3394_CR32","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1042\/BJ20141550","volume":"470","author":"M Rodriguez-Walker","year":"2015","unstructured":"Rodriguez-Walker M, Vilcaes AA, Garbarino-Pico E, Daniotti JL. Role of plasma-membrane-bound sialidase NEU3 in clathrin-mediated endocytosis. Biochem J. 2015;470:131\u201344.","journal-title":"Biochem J"},{"key":"3394_CR33","doi-asserted-by":"publisher","first-page":"13812","DOI":"10.1074\/jbc.RA120.012587","volume":"295","author":"J Gu","year":"2020","unstructured":"Gu J, Xu W, Jin N, Li L, Zhou Y, Chu D, et al. Truncation of tau selectively facilitates its pathological activities. J Biol Chem. 2020;295:13812\u201328.","journal-title":"J Biol Chem"},{"key":"3394_CR34","doi-asserted-by":"publisher","first-page":"24374","DOI":"10.1016\/S0021-9258(20)80536-5","volume":"268","author":"E Kopke","year":"1993","unstructured":"Kopke E, Tung YC, Shaikh S, Alonso AC, Iqbal K, Grundke-Iqbal I. Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. J Biol Chem. 1993;268:24374\u201384.","journal-title":"J Biol Chem"},{"key":"3394_CR35","doi-asserted-by":"publisher","first-page":"2245","DOI":"10.1111\/cns.13970","volume":"28","author":"L Li","year":"2022","unstructured":"Li L, Miao J, Chu D, Jin N, Tung YC, Dai CL, et al. Tau antibody 77G7 targeting microtubule binding domain suppresses proteopathic tau to seed tau aggregation. CNS Neurosci Ther. 2022;28:2245\u201359.","journal-title":"CNS Neurosci Ther"},{"key":"3394_CR36","doi-asserted-by":"crossref","unstructured":"Ji YR, Chen XL, Wang Z, Meek CJ, McLean JL, Yang Y, et al. Alzheimer\u2019s disease patient brain extracts induce multiple pathologies in novel vascularized neuroimmune organoids for disease modeling and drug discovery. Mol Psychiatr. 2025.","DOI":"10.1101\/2024.10.28.620680"},{"key":"3394_CR37","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1186\/s40478-022-01436-2","volume":"10","author":"N Jin","year":"2022","unstructured":"Jin N, Gu J, Wu R, Chu D, Tung YC, Wegiel J, et al. Tau seeding activity in various regions of down syndrome brain assessed by two novel assays. Acta Neuropathol Commun. 2022;10:132.","journal-title":"Acta Neuropathol Commun"},{"key":"3394_CR38","doi-asserted-by":"publisher","first-page":"15317","DOI":"10.1074\/jbc.M110.209296","volume":"286","author":"JL Guo","year":"2011","unstructured":"Guo JL, Lee VM. Seeding of normal Tau by pathological Tau conformers drives pathogenesis of Alzheimer-like tangles. J Biol Chem. 2011;286:15317\u201331.","journal-title":"J Biol Chem"},{"key":"3394_CR39","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1186\/s40478-022-01436-2","volume":"10","author":"N Jin","year":"2022","unstructured":"Jin N, Gu JL, Wu RZ, Chu DD, Tung YC, Wegiel J, et al. Tau seeding activity in various regions of down syndrome brain assessed by two novel assays. Acta Neuropathol Com. 2022;10:132.","journal-title":"Acta Neuropathol Com"},{"key":"3394_CR40","doi-asserted-by":"crossref","unstructured":"Bandopadhyay R. Sequential extraction of soluble and insoluble alpha-synuclein from Parkinsonian brains. J Vis Exp. 2016;107:e53415.","DOI":"10.3791\/53415-v"},{"key":"3394_CR41","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/j.brainres.2010.10.009","volume":"1366","author":"JC Carroll","year":"2010","unstructured":"Carroll JC, Rosario ER, Kreimer S, Villamagna A, Gentzschein E, Stanczyk FZ, et al. Sex differences in beta-amyloid accumulation in 3xTg-AD mice: role of neonatal sex steroid hormone exposure. Brain Res. 2010;1366:233\u201345.","journal-title":"Brain Res"},{"key":"3394_CR42","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1016\/S0896-6273(03)00434-3","volume":"39","author":"S Oddo","year":"2003","unstructured":"Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, et al. Triple-transgenic model of Alzheimer\u2019s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003;39:409\u201321.","journal-title":"Neuron"},{"key":"3394_CR43","doi-asserted-by":"publisher","first-page":"1676","DOI":"10.1016\/j.neuron.2024.02.017","volume":"112","author":"DH Zhang","year":"2024","unstructured":"Zhang DH, Zhang W, Ming C, Gao XH, Yuan HL, Lin XJ, et al. P-tau217 correlates with neurodegeneration in Alzheimer\u2019s disease, and targeting p-tau217 with immunotherapy ameliorates murine tauopathy. Neuron. 2024;112:1676\u201393.e12.","journal-title":"Neuron"},{"key":"3394_CR44","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1038\/s41401-020-0454-y","volume":"42","author":"YL Guo","year":"2021","unstructured":"Guo YL, Duan WJ, Lu DH, Ma XH, Li XX, Li Z, et al. Autophagy-dependent removal of alpha-synuclein: a novel mechanism of GM1 ganglioside neuroprotection against Parkinson\u2019s disease. Acta Pharmacol Sin. 2021;42:518\u201328.","journal-title":"Acta Pharmacol Sin"},{"key":"3394_CR45","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2023.1073774","volume":"15","author":"F Liu","year":"2023","unstructured":"Liu F, Wu R, Jin N, Chu D, Gu J, Tung YC, et al. Two simple assays for assessing the seeding activity of proteopathic tau. Front Aging Neurosci. 2023;15:1073774.","journal-title":"Front Aging Neurosci"},{"key":"3394_CR46","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/bs.pmbts.2017.12.005","volume":"156","author":"T Miyagi","year":"2018","unstructured":"Miyagi T, Takahashi K, Yamamoto K, Shiozaki K, Yamaguchi K. Biological and pathological roles of ganglioside sialidases. Prog Mol Biol Transl Sci. 2018;156:121\u201350.","journal-title":"Prog Mol Biol Transl Sci"},{"key":"3394_CR47","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/bs.pmbts.2018.01.001","volume":"156","author":"TA Li","year":"2018","unstructured":"Li TA, Schnaar RL. Congenital disorders of ganglioside biosynthesis. Prog Mol Biol Transl Sci. 2018;156:63\u201382.","journal-title":"Prog Mol Biol Transl Sci"},{"key":"3394_CR48","doi-asserted-by":"publisher","DOI":"10.1002\/alz.14418","volume":"21","author":"KF Falkon","year":"2025","unstructured":"Falkon KF, Danford L, Gutierrez Kuri E, Esquinca-Moreno P, Pe\u00f1a Se\u00f1eriz YL, Smith S, et al. Microglia internalize tau monomers and fibrils using distinct receptors but similar mechanisms. Alzheimers Dement. 2025;21:e14418.","journal-title":"Alzheimers Dement"},{"key":"3394_CR49","doi-asserted-by":"publisher","first-page":"E8508","DOI":"10.1073\/pnas.1712592114","volume":"114","author":"WT Li","year":"2017","unstructured":"Li WT, Hulswit RJG, Widjaja I, Raj VS, McBride R, Peng WJ, et al. Identification of sialic acid-binding function for the Middle East respiratory syndrome coronavirus spike glycoprotein. P Natl Acad Sci USA. 2017;114:E8508\u2013E8517.","journal-title":"P Natl Acad Sci USA"},{"key":"3394_CR50","doi-asserted-by":"publisher","first-page":"1062","DOI":"10.1038\/nm1095-1062","volume":"1","author":"K Yanagisawa","year":"1995","unstructured":"Yanagisawa K, Odaka A, Suzuki N, Ihara Y. GM1 ganglioside-bound amyloid beta-protein (A beta): a possible form of preamyloid in Alzheimer\u2019s disease. Nat Med. 1995;1:1062\u20136.","journal-title":"Nat Med"},{"key":"3394_CR51","doi-asserted-by":"publisher","first-page":"1979","DOI":"10.1021\/acschemneuro.2c00221","volume":"13","author":"DY Zhang","year":"2022","unstructured":"Zhang DY, Wang J, Fleeman RM, Kuhn MK, Swulius MT, Proctor EA, et al. Monosialotetrahexosylganglioside promotes early Abeta42 oligomer formation and maintenance. ACS Chem Neurosci. 2022;13:1979\u201391.","journal-title":"ACS Chem Neurosci"},{"key":"3394_CR52","doi-asserted-by":"publisher","first-page":"9303","DOI":"10.1021\/acs.jpclett.2c02362","volume":"13","author":"A Chakravorty","year":"2022","unstructured":"Chakravorty A, McCalpin SD, Sahoo BR, Ramamoorthy A, Brooks CL III. Free gangliosides can alter amyloid-beta aggregation. J Phys Chem Lett. 2022;13:9303\u20138.","journal-title":"J Phys Chem Lett"},{"key":"3394_CR53","doi-asserted-by":"publisher","first-page":"6896","DOI":"10.1039\/D0SC06426B","volume":"12","author":"Y Tian","year":"2021","unstructured":"Tian Y, Liang R, Kumar A, Szwedziak P, Viles JH. 3D-visualization of amyloid-beta oligomer interactions with lipid membranes by cryo-electron tomography. Chem Sci. 2021;12:6896\u2013907.","journal-title":"Chem Sci"},{"key":"3394_CR54","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1007\/s12264-021-00768-8","volume":"38","author":"CC Yang","year":"2022","unstructured":"Yang CC, Cheng Y, Yang HM, Chen Y, Wang YJ, Xu ZQ, et al. Peripheral delivery of ganglioside GM1 exacerbates the pathogenesis of alzheimer\u2019s disease in a mouse model. Neurosci Bull. 2022;38:95\u201398.","journal-title":"Neurosci Bull"},{"key":"3394_CR55","doi-asserted-by":"publisher","first-page":"868","DOI":"10.3390\/ijms21030868","volume":"21","author":"E Chiricozzi","year":"2020","unstructured":"Chiricozzi E, Lunghi G, Di Biase E, Fazzari M, Sonnino S, Mauri L. GM1 ganglioside is a key factor in maintaining the mammalian neuronal functions avoiding neurodegeneration. Int J Mol Sci. 2020;21:868.","journal-title":"Int J Mol Sci"},{"key":"3394_CR56","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1038\/nn1442","volume":"8","author":"JS Da Silva","year":"2005","unstructured":"Da Silva JS, Hasegawa T, Miyagi T, Dotti CG, Abad-Rodriguez J. Asymmetric membrane ganglioside sialidase activity specifies axonal fate. Nat Neurosci. 2005;8:606\u201315.","journal-title":"Nat Neurosci"},{"key":"3394_CR57","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1038\/s41580-024-00753-9","volume":"25","author":"CP Bravo","year":"2024","unstructured":"Bravo CP, Naguib SA, Gan L. Cellular and pathological functions of tau. Nat Rev Mol Cell Bio. 2024;25:845\u201364.","journal-title":"Nat Rev Mol Cell Bio"},{"key":"3394_CR58","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1001\/jamaneurol.2018.2505","volume":"76","author":"GS Gibbons","year":"2019","unstructured":"Gibbons GS, Lee VMY, Trojanowski JQ. Mechanisms of cell-to-cell transmission of pathological tau a review. Jama Neurol. 2019;76:101\u20138.","journal-title":"Jama Neurol"},{"key":"3394_CR59","doi-asserted-by":"publisher","first-page":"7532","DOI":"10.1074\/jbc.M611722200","volume":"282","author":"S Liang","year":"2007","unstructured":"Liang S, Wang M, Tapping RI, Stepensky V, Nawar HF, Triantafilou M, et al. Ganglioside GD1a is an essential coreceptor for Toll-like receptor 2 signaling in response to the B subunit of type IIb enterotoxin. J Biol Chem. 2007;282:7532\u201342.","journal-title":"J Biol Chem"},{"key":"3394_CR60","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1021\/jacs.6b09534","volume":"139","author":"C Hamark","year":"2017","unstructured":"Hamark C, Berntsson RPA, Masuyer G, Henriksson LM, Gustafsson R, Stenmark P, et al. Glycans confer specificity to the recognition of ganglioside receptors by botulinum neurotoxin a. J Am Chem Soc. 2017;139:218\u201330.","journal-title":"J Am Chem Soc"},{"key":"3394_CR61","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1186\/s13024-024-00786-w","volume":"19","author":"AT Marvian","year":"2024","unstructured":"Marvian AT, Strauss T, Tang QL, Tuck BJ, Keeling S, R\u00fcdiger D, et al. Distinct regulation of Tau Monomer and aggregate uptake and intracellular accumulation in human neurons. Mol Neurodegener. 2024;19:100.","journal-title":"Mol Neurodegener"},{"key":"3394_CR62","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1186\/s40478-019-0770-y","volume":"7","author":"P Weisov\u00e1","year":"2019","unstructured":"Weisov\u00e1 P, Cehl\u00e1r O, Skrabana R, Zilkov\u00e1 M, Filipc\u00edk P, Kov\u00e1cech B, et al. Therapeutic antibody targeting microtubule-binding domain prevents neuronal internalization of extracellular tau via masking neuron surface proteoglycans. Acta Neuropathol Com. 2019;7:129.","journal-title":"Acta Neuropathol Com"},{"key":"3394_CR63","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1021\/acs.accounts.3c00614","volume":"57","author":"X Chen","year":"2023","unstructured":"Chen X. Enabling chemoenzymatic strategies and enzymes for synthesizing sialyl glycans and sialyl glycoconjugates. Accounts Chem Res. 2023;57:234\u201346.","journal-title":"Accounts Chem Res"},{"key":"3394_CR64","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.4103\/1673-5374.385853","volume":"19","author":"D Chu","year":"2023","unstructured":"Chu D, Yang X, Wang J, Zhou Y, Gu JH, Miao J, et al. Tau truncation in the pathogenesis of Alzheimer\u2019s disease: a narrative review. Neural Regen Res. 2023;19:1221\u201332.","journal-title":"Neural Regen Res"},{"key":"3394_CR65","doi-asserted-by":"crossref","unstructured":"Fowler SL, Behr TS, Turkes E, O\u2019Brien DP, Cauhy PM, Rawlinson I, et al. Tau filaments are tethered within brain extracellular vesicles in Alzheimer\u2019s disease. Nat Neurosci. 2025;28:40\u20138.","DOI":"10.1038\/s41593-024-01801-5"},{"key":"3394_CR66","doi-asserted-by":"publisher","first-page":"6673","DOI":"10.1007\/s12035-019-1556-8","volume":"56","author":"E Chiricozzi","year":"2019","unstructured":"Chiricozzi E, Maggioni M, di Biase E, Lunghi G, Fazzari M, Loberto N, et al. The Neuroprotective Role of the GM1 Oligosaccharide, II(3)Neu5Ac-Gg(4), in Neuroblastoma Cells. Mol Neurobiol. 2019;56:6673\u2013702.","journal-title":"Mol Neurobiol"}],"container-title":["Molecular Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41380-025-03394-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41380-025-03394-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41380-025-03394-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T09:05:53Z","timestamp":1776762353000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41380-025-03394-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,15]]},"references-count":66,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["3394"],"URL":"https:\/\/doi.org\/10.1038\/s41380-025-03394-2","relation":{},"ISSN":["1359-4184","1476-5578"],"issn-type":[{"value":"1359-4184","type":"print"},{"value":"1476-5578","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,15]]},"assertion":[{"value":"20 February 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 November 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 December 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 December 2025","order":4,"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"}}]}}