{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:38:50Z","timestamp":1792607930565,"version":"4.5.0"},"reference-count":74,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2018,4,11]],"date-time":"2018-04-11T00:00:00Z","timestamp":1523404800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Tauopathies such as Alzheimer\u2019s disease (AD), frontotemporal lobar degeneration, or progressive supranuclear palsy constitute a group of brain disorders defined by neurodegeneration and the presence of tau aggregates in the affected brains regions. Tau is a microtubule-associated protein that accumulates in the cytosol under pathological conditions, steering the formation of aggregates or inclusions thought to be involved in the degeneration and neuronal death associated with these diseases. Despite a substantial and unmet medical need for novel, more effective disease-modifying therapies for the treatment of AD and tauopathies, the last couple of decades have seen numerous drug development undertakings primarily focused on \u03b2-amyloid, with disappointing results to date. On the other hand, tau-focused approaches have not received much attention until recently, notwithstanding that the presence of extensive tau pathology is fundamental for the disease and tau pathology shows a better correlation with impaired cognitive function than with amyloid pathology in AD patients. The last few years have brought us advances in our comprehension of tau biological functions beyond its well-established role as a microtubule-associated protein, unveiling novel physiological tau functions that may also be involved in pathogenesis and thus provide novel targets for therapeutic intervention. This review describes several emerging, encouraging therapeutic approaches aimed at tackling the underlying causes of tau pathology in AD and other tauopathies that have recently reached the clinical development stage.<\/jats:p>","DOI":"10.3390\/ijms19041160","type":"journal-article","created":{"date-parts":[[2018,4,11]],"date-time":"2018-04-11T12:16:50Z","timestamp":1523449010000},"page":"1160","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":141,"title":["An Overview on the Clinical Development of Tau-Based Therapeutics"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7016-5340","authenticated-orcid":false,"given":"Miguel","family":"Medina","sequence":"first","affiliation":[{"name":"Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Queen Sofia Foundation Alzheimer Center, CIEN Foundation, Carlos III Institute of Health, 28031 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,4,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.1073\/pnas.72.5.1858","article-title":"A protein factor essential for microtubule assembly","volume":"72","author":"Weingarten","year":"1975","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2739","DOI":"10.1083\/jcb.103.6.2739","article-title":"Tau protein function in living cells","volume":"103","author":"Drubin","year":"1986","journal-title":"J. Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1385\/NMM:2:2:151","article-title":"Axonal transport, tau protein, and neurodegeneration in Alzheimer\u2019s disease","volume":"2","author":"Terwel","year":"2002","journal-title":"Neuromol. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4913","DOI":"10.1073\/pnas.83.13.4913","article-title":"Abnormal phosphorylation of the microtubule-associated protein \u03c4 (tau) in Alzheimer cytoskeletal pathology","volume":"83","author":"Iqbal","year":"1986","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/0006-8993(74)90798-7","article-title":"Terry RD Protein changes in senile dementia","volume":"77","author":"Iqbal","year":"1974","journal-title":"Brain Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"E21","DOI":"10.3390\/biom6020021","article-title":"New features about Tau function and dysfunction","volume":"6","author":"Medina","year":"2016","journal-title":"Biomolecules"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/s40478-017-0489-6","article-title":"Atypical, non-standard functions of the microtubule associated Tau protein","volume":"5","author":"Sotiropoulos","year":"2017","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1007\/s12031-011-9593-4","article-title":"Pathogenesis of the tauopathies","volume":"45","author":"Goedert","year":"2001","journal-title":"J. Mol. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1126\/science.3122323","article-title":"The primary structure and heterogeneity of tau protein from mouse brain","volume":"239","author":"Lee","year":"1988","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/S1474-4422(13)70090-5","article-title":"Tau pathology and neurodegeneration","volume":"12","author":"Spillantini","year":"2013","journal-title":"Lancet Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1038\/31508","article-title":"Association of missense and 5\u2032-splice-site mutations in tau with the inherited dementia FTDP-17","volume":"393","author":"Hutton","year":"1998","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"20","DOI":"10.2174\/157488911794079091","article-title":"Recent developments in tau-based therapeutics for neurodegenerative diseases","volume":"6","author":"Medina","year":"2011","journal-title":"Recent Pat. CNS Drug Discov."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"113","DOI":"10.3389\/fncel.2014.00113","article-title":"The role of extracellular Tau in the spreading of neurofibrillary pathology","volume":"8","author":"Medina","year":"2014","journal-title":"Front. Cell. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1038\/nrd.2017.155","article-title":"Tau-based therapies in neurodegeneration: Opportunities and challenges","volume":"16","author":"Li","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1111\/j.1460-9568.2006.05226.x","article-title":"Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration","volume":"25","author":"Wang","year":"2007","journal-title":"Eur. J. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.molmed.2009.01.003","article-title":"Tau phosphorylation: The therapeutic challenge for neurodegenerative disease","volume":"15","author":"Hanger","year":"2009","journal-title":"Trends Mol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1586\/14737175.2015.1000864","article-title":"Further understanding of tau phosphorylation: Implications for therapy","volume":"15","author":"Medina","year":"2015","journal-title":"Expert Rev. Neurother."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"22042","DOI":"10.1074\/jbc.M112.436402","article-title":"Diaminothiazoles modify Tau phosphorylation and improve the tauopathy in mouse models","volume":"288","author":"Zhang","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.nurt.2008.05.006","article-title":"Tau-based treatment strategies in neurodegenerative diseases","volume":"5","author":"Schneider","year":"2008","journal-title":"Neurotherapeutics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1111\/j.1471-4159.2007.05194.x","article-title":"The GSK3 hypothesis of Alzheimer\u2019s disease","volume":"104","author":"Hooper","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1517\/14728222.2013.843670","article-title":"New Insights into the Role of Glycogen Synthase Kinase 3 in Alzheimer\u2019s Disease","volume":"18","author":"Medina","year":"2014","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1192\/bjp.bp.110.080044","article-title":"Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: Randomised controlled trial","volume":"198","author":"Forlenza","year":"2011","journal-title":"Br. J. Psychiatry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"24","DOI":"10.3389\/fnmol.2011.00024","article-title":"Modulation of GSK-3 as a Therapeutic Strategy on Tau Pathologies","volume":"4","author":"Medina","year":"2011","journal-title":"Front. Mol. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1074\/jbc.M111.306472","article-title":"Evidence for irreversible inhibition of glycogen synthase kinase-3\u03b2 by tideglusib","volume":"287","author":"Fuertes","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.nbd.2009.05.025","article-title":"A novel GSK-3\u03b2 inhibitor reduces Alzheimer\u2019s pathology and rescues neuronal loss in vivo","volume":"35","author":"Coma","year":"2009","journal-title":"Neurobiol. Dis."},{"key":"ref_26","first-page":"205","article-title":"Treatment of Alzheimer\u2019s disease with the GSK-3 inhibitor tideglusib: A pilot study","volume":"33","author":"Steinwachs","year":"2013","journal-title":"J. Alzheimers Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"75","DOI":"10.3233\/JAD-141959","article-title":"A phase II trial of tideglusib in Alzheimer\u2019s disease","volume":"45","author":"Lovestone","year":"2015","journal-title":"J. Alzheimers Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1002\/mds.25824","article-title":"A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy","volume":"29","author":"Tolosa","year":"2014","journal-title":"Mov. Disord."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1002\/mds.25815","article-title":"TAUROS MRI Investigators. Tideglusib reduces progression of brain atrophy in progressive supranuclear palsy in a randomized trial","volume":"29","author":"Huppertz","year":"2014","journal-title":"Mov. Disord."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/alzrt238","article-title":"Fyn kinase inhibition as a novel therapy for Alzheimer\u2019s disease","volume":"6","author":"Nygaard","year":"2014","journal-title":"Alzheimers Res. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s13195-015-0119-0","article-title":"A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer\u2019s disease","volume":"7","author":"Nygaard","year":"2015","journal-title":"Alzheimers Res. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2321","DOI":"10.2174\/092986708785909111","article-title":"Hyperphosphorylation of microtubule-associated protein tau: A promising therapeutic target for Alzheimer disease","volume":"15","author":"Gong","year":"2008","journal-title":"Curr. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"16","DOI":"10.3389\/fnmol.2014.00016","article-title":"Protein phosphatase 2A dysfunction in Alzheimer\u2019s disease","volume":"7","author":"Sontag","year":"2014","journal-title":"Front. Mol. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1038\/nm.3951","article-title":"Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits","volume":"21","author":"Min","year":"2015","journal-title":"Nat. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/nchembio.797","article-title":"Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation","volume":"8","author":"Yuzwa","year":"2012","journal-title":"Nat. Chem. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"P261","DOI":"10.1016\/j.jalz.2016.06.470","article-title":"; the PREVENT-AD Research Group. CSF markers of inflammation and Alzheimer\u2019s disease pathogenesis in the cognitively intact PREVENT-AD cohort","volume":"12","author":"Breitner","year":"2016","journal-title":"Alzheimers Dement."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"P1028","DOI":"10.1016\/j.jalz.2016.06.2125","article-title":"Pharmacokinetics and pharmacodynamics to support clinical studies of MK-8719: An O-GlcNAcase inhibitor for Progressive Supranuclear palsy","volume":"12","author":"Sandhu","year":"2016","journal-title":"Alzheimers Dement."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1038\/ng.859","article-title":"Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy","volume":"43","author":"Melhem","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"371","DOI":"10.15252\/emmm.201606664","article-title":"PERK activation mitigates tau pathology in vitro and in vivo","volume":"9","author":"Bruch","year":"2017","journal-title":"EMBO Mol. Med."},{"key":"ref_40","first-page":"114","article-title":"Emergence of BCR-ABL kinase domain mutations associated with newly diagnosed chronic myeloid leukemia: A meta-analysis of clinical trials of tyrosine kinase inhibitors","volume":"21","author":"Ursan","year":"2015","journal-title":"J. Manag. Care Spec. Pharm."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3541","DOI":"10.1091\/mbc.e14-06-1099","article-title":"Single-molecule tracking of tau reveals fast kiss-and-hop interaction with microtubules in living neurons","volume":"25","author":"Janning","year":"2014","journal-title":"Mol. Biol. Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2494","DOI":"10.1091\/mbc.e12-12-0858","article-title":"Amyloid-\u03b2 oligomers induce tau-independent disruption of BDNF axonal transport via calcineurin activation in cultured hippocampal neurons","volume":"24","author":"Ramser","year":"2013","journal-title":"Mol. Biol. Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"13861","DOI":"10.1523\/JNEUROSCI.3059-10.2010","article-title":"Epothilone D improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy","volume":"30","author":"Brunden","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1124\/jpet.107.130526","article-title":"A neuronal microtubule-interacting agent, NAPVSIPQ, reduces tau pathology and enhances cognitive function in a mouse model of Alzheimer\u2019s disease","volume":"325","author":"Matsuoka","year":"2008","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1159\/000348347","article-title":"AL-108-211 Study. A double-blind, placebo-controlled, ascending-dose, randomized study to evaluate the safety, tolerability and effects on cognition of AL-108 after 12 weeks of intranasal administration in subjects with mild cognitive impairment","volume":"35","author":"Morimoto","year":"2013","journal-title":"Dement. Geriatr. Cogn. Disord."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1016\/S1474-4422(14)70088-2","article-title":"Davunetide in patients with progressive supranuclear palsy: A randomised, double-blind, placebo-controlled phase 2\/3 trial","volume":"13","author":"Boxer","year":"2014","journal-title":"Lancet Neurol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4135","DOI":"10.1021\/jm3017317","article-title":"Progress and developments in tau aggregation inhibitors for Alzheimer disease","volume":"56","author":"Bulic","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1128\/AAC.00773-07","article-title":"Interactions of methylene blue with human disulfide reductases and their orthologues from Plasmodium falciparum","volume":"52","author":"Buchholz","year":"2008","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2325e7","DOI":"10.1016\/j.neurobiolaging.2010.12.012","article-title":"Lest we forget you\u2014Methylene blue","volume":"32","author":"Schirmer","year":"2011","journal-title":"Neurobiol. Aging"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"11213","DOI":"10.1073\/pnas.93.20.11213","article-title":"Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines","volume":"93","author":"Wischik","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"705","DOI":"10.3233\/JAD-142874","article-title":"Tau aggregation inhibitor therapy: An exploratory phase 2 study in mild or moderate Alzheimer\u2019s disease","volume":"44","author":"Wischik","year":"2015","journal-title":"J. Alzheimers Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2873","DOI":"10.1016\/S0140-6736(16)31275-2","article-title":"Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer\u2019s disease: A randomised, controlled, double-blind, parallel-arm, phase 3 trial","volume":"388","author":"Gauthier","year":"2016","journal-title":"Lancet"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"435","DOI":"10.3233\/JAD-170560","article-title":"Potential of Low Dose Leuco-Methylthioninium Bis(Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimer\u2019s Disease: Cohort Analysis as Modified Primary Outcome in a Phase III Clinical Trial","volume":"61","author":"Wilcock","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"ref_54","first-page":"S255","article-title":"A phase 3 trial of the tau and TDP-43 aggregation inhibitor, leuco-methylthioninium-bis (hydromethanesulfonate) (LMTM), for behavioural variant frontotemporal dementia (bvFTD)","volume":"138","author":"Feldman","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1007\/s40265-015-0529-0","article-title":"Tau Biology and Tau-Directed Therapies for Alzheimer\u2019s Disease","volume":"76","author":"Bakota","year":"2016","journal-title":"Drugs"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"203","DOI":"10.25100\/cm.v47i4.2640","article-title":"Amyloid-\u03b2 immunotherapy: The hope for Alzheimer disease?","volume":"47","author":"Lopera","year":"2016","journal-title":"Colomb. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/j.molmed.2015.03.003","article-title":"Tau immunotherapy for Alzheimer\u2019s disease","volume":"21","author":"Pedersen","year":"2015","journal-title":"Trends Mol. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1007\/s00401-017-1707-9","article-title":"Roles of tau protein in health and disease","volume":"133","author":"Guo","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1038\/nm0796-783","article-title":"Alzheimer\u2019s disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules","volume":"2","author":"Alonso","year":"1996","journal-title":"Nat. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1016\/j.jalz.2016.01.014","article-title":"Hyperphosphorylation determines both the spread and the morphology of tau pathology","volume":"12","author":"Hu","year":"2017","journal-title":"Alzheimers Dement."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s13195-018-0341-7","article-title":"Tau passive immunization blocks seeding and spread of Alzheimer hyperphosphorylated Tau-induced pathology in 3\u00d7 Tg-AD mice","volume":"10","author":"Dai","year":"2018","journal-title":"Alzheimers Res. Ther."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/S1474-4422(16)30331-3","article-title":"Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer\u2019s disease: A randomised, double-blind, placebo-controlled, phase 1 trial","volume":"16","author":"Novak","year":"2017","journal-title":"Lancet Neurol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/S1474-4422(12)70099-6","article-title":"The non-fluent\/agrammatic variant of primary progressive aphasia","volume":"11","author":"Grossman","year":"2012","journal-title":"Lancet Neurol."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Theunis, C., Crespo-Biel, N., Gafner, V., Pihlgren, M., Lopez-Deber, M.P., Reis, P., Hickman, D.T., Adolfsson, O., Chuard, N., and Ndao, D.M. (2013). Efficacy and safety of a liposome-based vaccine against protein Tau, assessed in tau.P301L mice that model tauopathy. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0072301"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/nrneurol.2014.253","article-title":"Intravenous immunoglobulin in neurology\u2014Mode of action and clinical efficacy","volume":"11","author":"Nimmerjahn","year":"2015","journal-title":"Nat. Rev. Neurol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.1212\/WNL.0000000000003904","article-title":"A phase 3 trial of IV immunoglobulin for Alzheimer disease","volume":"88","author":"Relkin","year":"2017","journal-title":"Neurology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.jneuroim.2017.09.011","article-title":"Characterization of isolated tau-reactive antibodies from the IVIG product, plasma of patients with Alzheimer\u2019s disease and cognitively normal individuals","volume":"313","author":"Krestova","year":"2017","journal-title":"J. Neuroimmunol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1159\/000440842","article-title":"Tau immunotherapy","volume":"16","author":"Sigurdsson","year":"2016","journal-title":"Neurodegener. Dis."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.neurobiolaging.2014.09.007","article-title":"Human secreted tau increases amyloid-\u03b2 production","volume":"36","author":"Bright","year":"2015","journal-title":"Neurobiol. Aging"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1038\/nrd4708","article-title":"Stem-cell discovery platforms yield first clinical candidates","volume":"14","author":"Mullard","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_71","first-page":"236","article-title":"Preclinical and Clinical Development of ABBV-8E12, a Humanized Anti-Tau Antibody, for Treatment of Alzheimer\u2019s Disease and Other Tauopathies","volume":"4","author":"West","year":"2017","journal-title":"J. Prev. Alzheimers Dis."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"P599","DOI":"10.1016\/j.jalz.2017.07.241","article-title":"Results of a phase 1, single ascending dose, placebo-controlled study of ABBV-8E12 in patients with Progressive Supranuclear Palsy and phase 2 study design in early Alzheimer\u2019s disease","volume":"13","author":"Budur","year":"2017","journal-title":"Alzheimers Dement."},{"key":"ref_73","first-page":"264","article-title":"Developing Disease-Modifying Treatments in Alzheimer\u2019s Disease\u2014A Perspective from Roche and Genentech","volume":"4","author":"Doody","year":"2017","journal-title":"J. Prev. Alzheimers Dis."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1016\/j.neurobiolaging.2014.11.022","article-title":"Tau immunization: A cautionary tale?","volume":"36","author":"Mably","year":"2015","journal-title":"Neurobiol. Aging"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/4\/1160\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:00:20Z","timestamp":1760194820000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/4\/1160"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,4,11]]},"references-count":74,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2018,4]]}},"alternative-id":["ijms19041160"],"URL":"https:\/\/doi.org\/10.3390\/ijms19041160","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,4,11]]}}}