Efficacy and Safety of A Liposome-Based Vaccine against Protein Tau, Assessed in Tau.P301L Mice That Model Tauopathy
Open accessAbstract
Progressive aggregation of protein Tau into oligomers and fibrils correlates with cognitive decline and synaptic dysfunction, leading to neurodegeneration in vulnerable brain regions in Alzheimer's disease. The unmet need of effective therapy for Alzheimer's disease, combined with problematic pharmacological approaches, led the field to explore immunotherapy, first against amyloid peptides and recently against protein Tau. Here we adapted the liposome-based amyloid vaccine that proved safe and efficacious, and incorporated a synthetic phosphorylated peptide to mimic the important phospho-epitope of protein Tau at residues pS396/pS404. We demonstrate that the liposome-based vaccine elicited, rapidly and robustly, specific antisera in wild-type mice and in Tau.P301L mice. Long-term vaccination proved to be safe, because it improved the clinical condition and reduced indices of tauopathy in the brain of the Tau.P301L mice, while no signs of neuro-inflammation or other adverse neurological effects were observed. The data corroborate the hypothesis that liposomes carrying phosphorylated peptides of protein Tau have considerable potential as safe and effective treatment against tauopathies, including Alzheimer's disease.
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Active tau immunization reduces tau pathology by targeting single or multiple phospho-epitopes, the amino terminus, full-length normal and mutant tau, or aggregated tau.
“Active tau immunization has been shown to reduce tau pathology by targeting single185, 187, 189–193 or multiple194 phospho-epitopes, the amino terminus195, full-length normal and mutant tau196, 197, or aggregated tau198.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [190]
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“5 months) with practically no survivors beyond age 12 months [37].”
BackgroundSelf-citationAlzheimer's disease: Old problem, new views from transgenic and viral models
Jaworski, T., Dewachter, I., Seymour, C. M., Borghgraef, P., Devijver, H., Kügler, S., & LEUVEN, F. V. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2010.03.005 · Cited by 49 · cited 6× · see citing works
“pre-clinical models for neuronal tauopathy [12,30–38].”
BackgroundInfluentialSelf-citationPihlgren, M., Silva, A. B., Madani, R., Giriens, V., Waeckerle‐Men, Y., Fettelschoss‐Gabriel, A., Hickman, D. T., López-Deber, M. P., Ndao, D. M., Vukicevic, M., et al. (2012) · Blood · doi:10.1182/blood-2012-02-413831 · Cited by 44 · cited 2× · see citing works
“Cytokine production of pTau/Tau peptides or Tau proteinspecific T cells was assessed by ELISPOT as previously described [24].”
BackgroundMethodSelf-citationMenuet, C., Cazals, Y., Gestreau, C., Borghgraef, P., Gielis, L., Dutschmann, M., LEUVEN, F. V., & Hilaire, G. (2011) · PLoS ONE · doi:10.1371/journal.pone.0025770 · Cited by 44 · see citing works
Self-citationMaurin, H., Seymour, C. M., Lechat, B., Borghgraef, P., Devijver, H., Jaworski, T., Schmidt, M. V., Kügler, S., & LEUVEN, F. V. (2013) · PLoS ONE · doi:10.1371/journal.pone.0063589 · Cited by 36 · cited 5× · see citing works
“pre-clinical models for neuronal tauopathy [12,30–38].”
BackgroundInfluentialSelf-citationMenuet, C., Borghgraef, P., Matarazzo, V. A., Gielis, L., Lajard, A.-M., Voituron, N., Gestreau, C., Dutschmann, M., LEUVEN, F. V., & Hilaire, G. (2011) · Respiratory Physiology & Neurobiology · doi:10.1016/j.resp.2011.06.030 · Cited by 35 · cited 5× · see citing works
“pre-clinical models for neuronal tauopathy [12,30–38].”
BackgroundInfluentialSelf-citationRECENT DEVELOPMENTS IN ALZHEIMER’S DISEASE
Cras, P. P. (2001) · Acta Clinica Belgica · doi:10.1179/acb.2001.040 · Cited by 33 · see citing works
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Immunotherapy and Neuroimmunology in Alzheimer‘s Disease: a Perspective from The Blood–Brain Barrier
Banks, W. A. (2009) · Immunotherapy · doi:10.2217/imt.09.72 · Cited by 15 · cited 2× · see citing works
“Moreover, in AD and other neurological disorders, the BBB is compromised which might allow antibodies to enter the CNS more readily [47–53].”
BackgroundBinding specificity of monoclonal antibody AD2: influence of the phosphorylation state of tau
Torreilles, F., Roquet, F., Granier, C., Pau, B., & Mourton-Gilles, C. (2000) · Molecular Brain Research · doi:10.1016/s0169-328x(00)00073-5 · Cited by 10 · cited 1× · see citing works
“AD2 and PHF1 among others, are located in this region [25–29].”
BackgroundFuture of Immunotherapy: A Call for Comparative Immunology
Marincola, F. M. (2008) · Immunotherapy · doi:10.2217/1750743x.1.1.1 · Cited by 5 · see citing works
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Tau-targeting therapies for Alzheimer disease
Congdon, E. E., & Sigurdsson, E. M. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0013-z · Cited by 1,113 · see citing works
Peptide-Based Vaccines: Current Progress and Future Challenges
Malonis, R. J., Lai, J. R., & Vergnolle, O. (2020) · Chemical Reviews · doi:10.1021/acs.chemrev.9b00472 · Cited by 602 · see citing works
Alzheimer’s disease: Recent treatment strategies
Vaz, M., & Silvestre, S. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173554 · Cited by 547 · see citing works
Update on Alzheimer’s Disease Therapy and Prevention Strategies
Graham, W. V., Bonito-Oliva, A., & Sakmar, T. P. (2017) · Annual Review of Medicine · doi:10.1146/annurev-med-042915-103753 · Cited by 506 · see citing works
Therapeutic strategies for Alzheimer's disease in clinical trials
Godyń, J., Jończyk, J., Panek, D., & Malawska, B. (2015) · Pharmacological Reports · doi:10.1016/j.pharep.2015.07.006 · Cited by 454 · see citing works
“Phase I clinical trials have started and ACI-35 is currently undergoing phase Ib clinical trials in patients suffering from this common form of dementia [56,59].”
BackgroundDrug candidates in clinical trials for Alzheimer’s disease
Hung, S.-Y., & Fu, W.-M. (2017) · Journal of Biomedical Science · doi:10.1186/s12929-017-0355-7 · Cited by 420 · see citing works
“Enhancement of phosphorylated-tau clearance by active immunotherapy High-affinity antibodies against phosphorylated-tau from active immunization of phosphorylated-tau is one approach, such as AADvac-1, which contains synthetic tau294-305 peptides, and also ACI-35, which contains phosphorylated S396 and S404 tau fragme…”
BackgroundVieira, D., & Gamarra, L. (2016) · International Journal of Nanomedicine · doi:10.2147/ijn.s117210 · Cited by 427 · see citing works
“Lastly, different liposome-based vaccines were developed and directed toward Aβ plaques(115,116) and tau.(114) Liposomes in the treatment of Parkinson’s disease PD affects 4 million people worldwide.”
BackgroundTau Aggregation and Its Interplay with Amyloid-β
Nisbet, R. M., Polanco, J.-C., Ittner, L. M., & Götz, J. (2015) · Acta Neuropathologica · doi:10.1007/s00401-014-1371-2 · Cited by 359 · see citing works
Tauopathies: new perspectives and challenges
Zhang, Y., Wu, K.-M., Yang, L., Dong, Q., & Yu, J.-T. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00533-z · Cited by 323 · see citing works
GSK-3 and tau: a key duet in Alzheimer’s disease
Sayas, C. L., & Ávila, J. (2021) · Cells · doi:10.3390/cells10040721 · Cited by 314 · see citing works
“ACI-35 elicits a rapid and robust immune response in preclinical studies in transgenic tau mice and a reduction in tau pathology [204].”
BackgroundA walk through tau therapeutic strategies
Jadhav, S., Ávila, J., Schöll, M., Kovács, G. G., Kövari, E., Škrabana, R., Evans, L., Kontseková, E., Malawska, B., de Silva, R., et al. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0664-z · Cited by 286 · see citing works
Tau immunotherapy for Alzheimer's disease
Pedersen, J. T., & Sigurdsson, E. M. (2015) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2015.03.003 · Cited by 247 · see citing works
Kontseková, E., Žilka, N., Kováčech, B., Novák, P., & Novák, M. (2014) · Alzheimer s Research & Therapy · doi:10.1186/alzrt278 · Cited by 248 · see citing works
“Several independent studies have shown that active and passive immunisation approaches were effective in reducing the burden of neurofibrillary tangles (NFTs) in the brain, slowing the progression of the behavioural phenotype or delaying the onset of motor function decline and weight loss in mouse models of tau tangle…”
Xia, Y., Prokop, S., & Giasson, B. I. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00460-5 · Cited by 218 · see citing works
“In C57/BL6 and tau-P301L transgenic mice [196], injection of the ACI-35 peptide generated a robust immune response, yielding multiple antibodies that are specific for p-tau and react with tau inclusions [197].”
BackgroundRojo, A. I., Pajares, M., Rada, P., Núñez, Á., Nevado‐Holgado, A. J., Killick, R., LEUVEN, F. V., Ribé, E. M., Lovestone, S., Yamamoto, M. P., et al. (2017) · Redox Biology · doi:10.1016/j.redox.2017.07.006 · Cited by 216 · see citing works
Intersection of pathological tau and microglia at the synapse
Vogels, T., Murgoci, A.-N., & Hromádka, T. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0754-y · Cited by 197 · see citing works
Tau-Centric targets and drugs in clinical development for the treatment of alzheimer's disease
Panza, F., Solfrizzi, V., Seripa, D., Imbimbo, B. P., Lozupone, M., Santamato, A., Zecca, C., Barulli, M. R., Bellomo, A., Pilotto, A., et al. (2016) · BioMed Research International · doi:10.1155/2016/3245935 · Cited by 195 · see citing works
“[83] C.”
BackgroundInfluentialTau passive immunization inhibits not only tau but also Aβ pathology
Dai, C., Tung, Y. C., Liu, F., Gong, C., & Iqbal, K. (2017) · Alzheimer s Research & Therapy · doi:10.1186/s13195-016-0227-5 · Cited by 186 · see citing works
“Active immunization with tau phosphopeptides reduces tau pathology [16–22] and rescues or slows cognitive decline in rodents [16, 19, 21, 22].”
Novel Therapeutic Approaches for Alzheimer’s Disease: An Updated Review
Yu, T.-W., Lane, H., & Lin, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22158208 · Cited by 182 · see citing works
“In animal studies, ACI-35 induced a rapid immune response and decreased phosphorylated tau in tau transgenic mice within 12 weeks [188].”
BackgroundTau Biology and Tau-Directed Therapies for Alzheimer’s Disease
Bakota, L., & Brandt, R. (2016) · Drugs · doi:10.1007/s40265-015-0529-0 · Cited by 170 · see citing works
Peng, Y., Jin, H., Xue, Y.-H., Chen, Q., Yao, S., Du, M., & Liu, S. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1206572 · Cited by 176 · see citing works
“ACI-35 decreased soluble and insoluble Tau in tau-transgenic mouse models (Theunis et al., 2013).”
BackgroundLimorenko, G., & Lashuel, H. A. (2021) · Chemical Society Reviews · doi:10.1039/d1cs00127b · Cited by 162 · see citing works
Passive immunotherapies targeting Aβ and tau in Alzheimer's disease
Plotkin, S. S., & Cashman, N. R. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.105010 · Cited by 156 · see citing works
An Overview on the Clinical Development of Tau-Based Therapeutics
Medina, M. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19041160 · Cited by 156 · see citing works
“Results showed a satisfactory safety and tolerability profile that supported further multiple-dose testing in patients with PSP, prompting a phase II clinical trial evaluating the efficacy and safety of ABBV-8E12 after 52 weeks in PSP subjects, which is currently recruiting (NCT02985879).”
BackgroundInfluentialCastillo-Carranza, D. L., Guerrero-Muñoz, M. J., Sengupta, U., Hernandez, C., Barrett, A. D. T., Dineley, K., & Kayed, R. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.4989-14.2015 · Cited by 149 · see citing works
“…most part, been directed at specific phosphorylated tau epitopes (Boimel et al., 2010; Boutajangout et al., 2010; Bi et al., 2011; Chai et al., 2011; Troquier et al., 2012; Rozenstein-Tsalkovich et al., 2013; Theunis et al., 2013; Yanamandra et al., 2013; d’Abramo et al., 2013; Walls et al., 2014).”
BackgroundRajasekhar, K., & Govindaraju, T. (2018) · RSC Advances · doi:10.1039/c8ra03620a · Cited by 150 · see citing works
Novak, P., Schmidt, R., Kontsekova, E., Kovacech, B., Smolek, T., Katina, S., Fialova, L., Prcina, M., Parrak, V., Dal-Bianco, P., et al. (2018) · Alzheimer's Research & Therapy · doi:10.1186/s13195-018-0436-1 · Cited by 147 · see citing works
Therapy and clinical trials in frontotemporal dementia: past, present, and future
Tsai, R. M., & Boxer, A. L. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13640 · Cited by 145 · see citing works
“Active immunization in transgenic mouse models with human tau pathology have been shown to have reduced tau pathology and improved performance on sensorimotor testing (Asuni et al. 2007; Theunis et al. 2013).”
Vaquer‐Alicea, J., Diamond, M. I., & Joachimiak, Ł. A. (2021) · Acta Neuropathologica · doi:10.1007/s00401-021-02301-7 · Cited by 134 · see citing works
Alzheimer's Disease: The Role of Microglia in Brain Homeostasis and Proteopathy
Clayton, K. A., Enoo, A. A. V., & Ikezu, T. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00680 · Cited by 132 · see citing works
“In hTau mice, prior to the time of expected significant neuronal loss, TREM2 KO was reported to increase the deposition of hyperphosphorylated tau and promote a less homeostatic microglial phenotype (Bemiller et al., 2017).”
BackgroundInfluentialNew Insights Into Drug Discovery Targeting Tau Protein
Soeda, Y., & Takashima, A. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.590896 · Cited by 133 · see citing works
“This vaccine also improved body weight loss and clasping frequency and survival (Theunis et al., 2013).”
BackgroundValera, E., Spencer, B. J., & Masliah, E. (2015) · Neurotherapeutics · doi:10.1007/s13311-015-0397-z · Cited by 129 · see citing works
“ACI-35 I Fragments (pS396, pS404) AC Immune SA [86]”
BackgroundKontsekova, E., Zilka, N., Kovacech, B., Skrabana, R., & Novak, M. (2014) · Alzheimer's Research & Therapy · doi:10.1186/alzrt277 · Cited by 112 · see citing works
“Several independent studies have shown that either active or passive immunotherapy could prevent tau aggregation or clear tau aggregates and reduce tau hyperphosphorylation [22-24,26,59-62].”
BackgroundPrecision pharmacology for Alzheimer’s disease
Hampel, H. J., Vergallo, A., Aguilar, L. F., Benda, N., Broich, K., Cuello, A. C., Cummings, J. L., Dubois, B., Federoff, H. J., Fiandaca, M. S., et al. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.02.014 · Cited by 112 · see citing works
Progressive supranuclear palsy: Advances in diagnosis and management
Coughlin, D. G., & Litvan, I. (2020) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2020.04.014 · Cited by 113 · see citing works
Immunotherapies for Neurodegenerative Diseases
Mortada, I., Farah, R., Nabha, S. M., Ojcius, D. M., Fares, Y., Almawi, W. Y., & Sadier, N. S. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.654739 · Cited by 112 · see citing works
“The evaluation in test animals, wild-type C57BL/6, and P301L, indicated a positive immunogenic activity specifically targeting pathological phosphorylated tau species with no neurological side effects or inflammation of neural tissue (182).”
BackgroundTau-Based Therapeutics for Alzheimer’s Disease: Active and Passive Immunotherapy
Panza, F., Solfrizzi, V., Seripa, D., Imbimbo, B. P., Lozupone, M., Santamato, A., Tortelli, R., Galizia, I., Prete, C., Daniele, A., et al. (2016) · Immunotherapy · doi:10.2217/imt-2016-0019 · Cited by 105 · see citing works
Advances and considerations in AD tau-targeted immunotherapy
Bittar, A., Bhatt, N. N., & Kayed, R. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104707 · Cited by 105 · see citing works
Pathological Changes of Tau Related to Alzheimer’s Disease
Chu, D., & Liu, F. (2018) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.8b00457 · Cited by 103 · see citing works
Pervin, Z., & Stephen, J. M. (2021) · AIMS neuroscience · doi:10.3934/neuroscience.2021021 · Cited by 107 · see citing works
Rao, M. V., McBrayer, M. K., Campbell, J., Kumar, A., Hashim, A. T., Sershen, H. W., Stavrides, P. H., Ohno, M., Hutton, M., & Nixon, R. A. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.1132-14.2014 · Cited by 99 · see citing works
Active immunotherapy options for Alzheimer’s disease
Winblad, B. G., Graf, A., Riviere, M., Andreasen, N., & Ryan, J. M. (2014) · Alzheimer s Research & Therapy · doi:10.1186/alzrt237 · Cited by 100 · see citing works
“P301L transgenic mice, ACI-35 elicited rapid and robust polyclonal antibody responses specific for phosphorylated tau [55].”
BackgroundArmy Liposome Formulation (ALF) family of vaccine adjuvants
Alving, C. R., Peachman, K. K., Matyas, G. R., Rao, M., & Beck, Z. (2020) · Expert Review of Vaccines · doi:10.1080/14760584.2020.1745636 · Cited by 98 · see citing works
“Previous clinical studies have also shown that ALF-type adjuvants are effective in candidate vaccines to meningitis caused by group B Neisseria meningitidis [84], and also in a variety of immunotherapeutic cancer vaccines [85–87]; and an ALF-type adjuvant is included in two candidate therapeutic Alzheimer’s disease va…”
ResultTargeting tau: clinical trials and novel therapeutic approaches
VandeVrede, L., Boxer, A. L., & Polydoro, M. (2020) · Neuroscience Letters · doi:10.1016/j.neulet.2020.134919 · Cited by 90 · see citing works
Current Status of Clinical Trials on Tau Immunotherapies
Ji, C., & Sigurdsson, E. M. (2021) · Drugs · doi:10.1007/s40265-021-01546-6 · Cited by 96 · see citing works
Modulation of Brain Hyperexcitability: Potential New Therapeutic Approaches in Alzheimer’s Disease
Toniolo, S., Sen, A., & Husain, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239318 · Cited by 94 · see citing works
“Active immunotherapies include AADvac1 [99], and ACI-35 [100].”
BackgroundImmunotherapies for Aging-Related Neurodegenerative Diseases—Emerging Perspectives and New Targets
Kwon, S., Iba, M., Kim, C., & Masliah, E. (2020) · Neurotherapeutics · doi:10.1007/s13311-020-00853-2 · Cited by 92 · see citing works
Tau immunotherapies: Lessons learned, current status and future considerations
Sandusky-Beltran, L. A., & Sigurdsson, E. M. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.108104 · Cited by 90 · see citing works
Ten Years of Tau-Targeted Immunotherapy: The Path Walked and the Roads Ahead
Novak, P., Kontsekova, E., Zilka, N., & Novak, M. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00798 · Cited by 87 · see citing works
“: (Kontsekova et al., 2014a,Kontsekova et al., 2014b; Novak et al., 2017) SHR72 rats (tau 151-391/4R), SHR background R3/m4 mice (tau 151-391/34R), C57BL/6 background ACI-35 Active pS396 (some sources additionally mention pS404) Tau pS396 with a conformation that is typically present in the brain of tauopathy patients…”
BackgroundInfluentialDrug development for Alzheimer’s disease: Review
Lao, K., Ji, N., Zhang, X., Qiao, W., Tang, Z., & Gou, X. (2019) · Journal of drug targeting · doi:10.1080/1061186x.2018.1474361 · Cited by 86 · see citing works
“[79] Theunis C, Crespo-Biel N, Gafner V, et al.”
BackgroundTauopathies: Deciphering Disease Mechanisms to Develop Effective Therapies
Silva, M. C., & Haggarty, S. J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21238948 · Cited by 87 · see citing works
Sigurdsson, E. M. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-179937 · Cited by 76 · see citing works
Microtubule-associated protein tau as a therapeutic target in Alzheimer's disease
Iqbal, K., Gong, C., & Liu, F. (2014) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2014.870156 · Cited by 76 · see citing works
“Several labs have since reported successful removal of abnormally hyperphosphorylated tau, both by active and passive tau immunization [109-111].”
BackgroundA critical appraisal of tau‐targeting therapies for primary and secondary tauopathies
Imbimbo, B. P., Ippati, S., Watling, M., & Balducci, C. (2021) · Alzheimer s & Dementia · doi:10.1002/alz.12453 · Cited by 72 · see citing works
Passive immunotherapy of tauopathy targeting pSer413‐tau: a pilot study in mice
Umeda, T., Eguchi, H., Kunori, Y., Matsumoto, Y., Taniguchi, T., Mori, H., & Tomiyama, T. (2015) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.171 · Cited by 73 · see citing works
Gerson, J. E., Castillo‐Carranza, D. L., & Kayed, R. (2014) · ACS Chemical Neuroscience · doi:10.1021/cn500143n · Cited by 73 · see citing works
Modulation of Disordered Proteins with a Focus on Neurodegenerative Diseases and Other Pathologies
Martinelli, A. H. S., Lopes, F. C., John, E. B. D. O., Carlini, C. R., & Ligabue‐Braun, R. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20061322 · Cited by 97 · see citing works
“Phase I clinical trial of ABBV-8E12, one of such humanized monoclonal antibodies [312], revealed a satisfactory safety profile in 30 patients with the progressive supranuclear palsy tauopathy, receiving single doses (2.”
BackgroundThe Role of P2X7 Receptor in Alzheimer’s Disease
Francistiová, L., Bianchi, C., Lauro, C. D., Sebastián‐Serrano, Á., de Diego-García, L., Kobolák, J., Dinnyés, A., & Dı́az-Hernández, M. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.00094 · Cited by 69 · see citing works
Tau immunotherapies for Alzheimer’s disease
Hoskin, J. L., Sabbagh, M. N., Al-Hasan, Y. M., & Decourt, B. (2019) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2019.1619694 · Cited by 68 · see citing works
“off-target inflammatory response, as assessed by quantification of inflammatory markers [68,69].”
Backgroundd’Abramo, C., D'adamio, L., & Giliberto, L. (2020) · Journal of Personalized Medicine · doi:10.3390/jpm10030116 · Cited by 68 · see citing works
“An active immunization approach against tau is currently under way as well [96,97].”
BackgroundDrug Delivery Systems as a Strategy to Improve the Efficacy of FDA-Approved Alzheimer’s Drugs
Nunes, D., Loureiro, J. A., & Pereira, M. C. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14112296 · Cited by 68 · see citing works
Tau Immunotherapies for Alzheimer’s Disease and Related Tauopathies: Progress and Potential Pitfalls
Sigurdsson, E. M. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-189010 · Cited by 67 · see citing works
Harnessing neuroplasticity: modern approaches and clinical future
Sasmita, A. O., Kuruvilla, J., & Ling, A. P. K. (2018) · International Journal of Neuroscience · doi:10.1080/00207454.2018.1466781 · Cited by 65 · see citing works
“[105] RG7345 Chronic immunization detectable in lysosomes via lipid rafts reduces tau/pS422 pathology.”
BackgroundAntibody-DerivedIn VivoImaging of Tau Pathology
Krishnaswamy, S., Lin, Y., Rajamohamedsait, W. J., Rajamohamedsait, H. B., Krishnamurthy, P., & Sigurdsson, E. M. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.2755-14.2014 · Cited by 62 · see citing works
Targeting aging and age-related diseases with vaccines
Wu, R., Sun, F., Zhang, W., Ren, J., & Liu, G.-H. (2024) · Nature Aging · doi:10.1038/s43587-024-00597-0 · Cited by 66 · see citing works
Agadjanyan, M. G., Petrovsky, N., & Ghochikyan, A. (2015) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2015.06.1884 · Cited by 65 · see citing works
“Passive immunization with anti-tau antibodies specific to p-tau antigenic determinants similarly reduced tau pathology and improved motor function of JNPL3 mice [144,151,152].”
BackgroundTau-targeting therapy in Alzheimer’s disease: Critical advances and future opportunities
Guo, Y., Li, S., Zeng, L.-H., & Tan, J. (2022) · Ageing and Neurodegenerative Diseases · doi:10.20517/and.2022.16 · Cited by 61 · see citing works
Developing therapeutic vaccines against Alzheimer’s disease
Wısnıewskı, T., & Drummond, E. (2015) · Expert Review of Vaccines · doi:10.1586/14760584.2016.1121815 · Cited by 58 · see citing works
“(AADVac1) or phosphorylated tau (ACI-35) have entered phase I testing [102,103] (www.”
BackgroundGhosh, S., Durgvanshi, S., Agarwal, S., Raghunath, M., & Sinha, J. K. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200429011823 · Cited by 57 · see citing works
“It entered a Phase 1b trial in 2015 with the objective of testing its efficacy against mild to moderate AD patients [56, 57].”
Sigurdsson, E. M. (2016) · Neurodegenerative Diseases · doi:10.1159/000440842 · Cited by 56 · see citing works
Calpain-mediated tau fragmentation is altered in Alzheimer’s disease progression
Chen, H.-H., Liu, P., Auger, P., Lee, S.-H., Adolfsson, O., Rey-Bellet, L., Lafrance-Vanasse, J., Friedman, B. A., Pihlgren, M., Muhs, A., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-35130-y · Cited by 51 · see citing works
Self-citationExtracellular vesicles and their synthetic analogues in aging and age-associated brain diseases
Smith, J. A., Leonardi, T., Huang, B., Iraci, N., Vega, B., & Pluchino, S. (2014) · Biogerontology · doi:10.1007/s10522-014-9510-7 · Cited by 53 · see citing works
“…peptides mimicking pathological epitopes of Ab or Tau with the intent of eliciting a robust and specific antibody response against the toxic form of the peptide and a subsequent clinical improvement in disease models (Hickman et al. 2011; Muhs et al. 2007; Nicolau et al. 2002; Theunis et al. 2013).”
BackgroundCellular senescence and other age-related mechanisms in skeletal diseases
Li, K., Hu, S., & Chen, H. (2025) · Bone Research · doi:10.1038/s41413-025-00448-7 · Cited by 58 · see citing works
Ceyzériat, K., Zilli, T., Millet, P., Frisoni, G. B., Garibotto, V., & Tournier, B. B. (2020) · Current Alzheimer Research · doi:10.2174/1567205017666200304085513 · Cited by 53 · see citing works
Morató, X., Pytel, V., Jofresa, S., Ruiz, A., & Boada, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23169305 · Cited by 53 · see citing works
“The vaccine contains a synthetic tau fragment phosphorylated at residues S396 and S404 anchored into a lipid bilayer [127].”
BackgroundAgadjanyan, M. G., Zagorski, K., Petrushina, I., Davtyan, H., Kazarian, K., Antonenko, M., Davis, J. L., Bon, C., Blurton-Jones, M. M., Cribbs, D. H., et al. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0172-1 · Cited by 53 · see citing works
“Currently, two active vaccines (AADvac1 [80, 81] and ACI-35 [79]) are being tested in clinical trials with AD patients, and two humanized versions of anti-tau antibodies have been reported to have advanced to clinical testing in subjects with progressive supranuclear palsy (NCT02494024, NCT02460094, NCT02658916).”
BackgroundHighly specific and selective anti‐pS396‐tau antibody C10.2 targets seeding‐competent tau
Rosenqvist, N., Asuni, A. A., Andersson, C. R., Christensen, S., Daechsel, J. C. A., Egebjerg, J., Falsig, J., Helboe, L., Jul, P., Kartberg, F., et al. (2018) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1016/j.trci.2018.09.005 · Cited by 51 · see citing works
Qß Virus-like particle-based vaccine induces robust immunity and protects against tauopathy
Maphis, N. M., Peabody, J., Crossey, E., Jiang, S., Ahmad, F. A. J., Álvarez, M. J., Mansoor, S. K., Yaney, A., Yang, Y., Sillerud, L. O., et al. (2019) · npj Vaccines · doi:10.1038/s41541-019-0118-4 · Cited by 48 · see citing works
“Two active immunotherapies targeting pTau that rely on a similar strategy are now in Phase I clinical trials: AADvac1, a tau peptide 294–305 linked to keyhole limpet hemocyanin (KLH) and administered with an alum adjuvant,(35) and ACI-35, a 16-amino acid tetra-palmitoylated phosphorylated tau peptide (encompassing the…”
MethodTau-directed approaches for the treatment of Alzheimer’s disease: focus on leuco-methylthioninium
Seripa, D., Solfrizzi, V., Imbimbo, B. P., Daniele, A., Santamato, A., Lozupone, M., Zuliani, G., Greco, A., Logroscino, G., & Panza, F. (2016) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.2016.1140039 · Cited by 50 · see citing works
Rajamohamedsait, H., Rasool, S., Rajamohamedsait, W., Lin, Y., & Sigurdsson, E. M. (2017) · Scientific Reports · doi:10.1038/s41598-017-17313-1 · Cited by 49 · see citing works
NAKAI, T., Yamada, K., & Mizoguchi, H. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115549 · Cited by 52 · see citing works
“Hyperphosphorylated tau vaccines were also developed using AD model mice that overexpress mutant human tau, but their effects have yet to be confirmed in clinical trials [221,222].”
BackgroundDiagnosis and Treatment of Alzheimer’s Disease:
Bomasang-Layno, E., & Bronsther, R. (2021) · Delaware Journal of Public Health · doi:10.32481/djph.2021.09.009 · Cited by 52 · see citing works
Kaur, P., Khera, A., Alajangi, H. K., Sharma, A., Jaiswal, P. K., Singh, G., & Barnwal, R. P. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-03164-z · Cited by 53 · see citing works
Passive Immunization in JNPL3 Transgenic Mice Using an Array of Phospho-Tau Specific Antibodies
d’Abramo, C., Acker, C. M., Jimenez, H. T., & Davies, P. (2015) · PLoS ONE · doi:10.1371/journal.pone.0135774 · Cited by 48 · see citing works
Rosenberg, R. N., Fu, M., & Lambracht‐Washington, D. (2018) · Alzheimer s Research & Therapy · doi:10.1186/s13195-018-0441-4 · Cited by 48 · see citing works
NPT088 reduces both amyloid‐β and tau pathologies in transgenic mice
Levenson, J. M., Schroeter, S., Carroll, J. C., Cullen, V., Asp, E., Proschitsky, M., Chung, C. H. ‐., Gilead, S., Nadeem, M., Dodiya, H. B., et al. (2016) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2016.06.004 · Cited by 47 · see citing works
Disentangling tau: One protein, many therapeutic approaches
Lane‐Donovan, C., & Boxer, A. L. (2024) · Neurotherapeutics · doi:10.1016/j.neurot.2024.e00321 · Cited by 44 · see citing works
Katsinelos, T., Tuck, B. J., Mukadam, A. S., & McEwan, W. A. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01139 · Cited by 44 · see citing works
“Vaccination conferred a reduction in levels of soluble and insoluble tau phosphorylated at S396 in mice transgenic for human P301L tau (91).”
BackgroundInfluentialRecent developments with tau-based drug discovery
Iqbal, K., Liu, F., & Gong, C. (2018) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2018.1445084 · Cited by 44 · see citing works
“passive tau immunizations but the results of these trials have not yet been reported; the active immunization, which was carried out in collaboration with Janssen Pharmaceuticals, employed pSer 396/404 peptide in a liposome adjuvant [135].”
MethodRecent advancements toward therapeutic vaccines against Alzheimer’s disease
Herline, K., Drummond, E., & Wısnıewskı, T. (2018) · Expert Review of Vaccines · doi:10.1080/14760584.2018.1500905 · Cited by 44 · see citing works
“Preclinical testing of ACI-35 proved safe, elicited strong antibody titers to phosphorylated tau and reduced levels of both soluble and insoluble phosphorylated tau in a mouse model for tau pathology [95].”
BackgroundGoodwin, M. S., Sinyavskaya, O., Burg, F., O’Neal, V., Ceballos‐Diaz, C., Cruz, P. E., Lewis, J. M., Giasson, B. I., Davies, P., Golde, T. E., et al. (2020) · Molecular Therapy · doi:10.1016/j.ymthe.2020.10.007 · Cited by 42 · see citing works
Vaccination strategies in tauopathies and synucleinopathies
Braczynski, A. K., Schulz, J. B., & Bach, J. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.14207 · Cited by 43 · see citing works
“Later on, the Rosenmann group developed a vaccine consisting of phosphorylated tau peptides (Boimel et al. 2010).”
BackgroundResultInfluentialModification of the gut microbiome to combat neurodegeneration
Sasmita, A. O. (2019) · Reviews in the Neurosciences · doi:10.1515/revneuro-2019-0005 · Cited by 46 · see citing works
The past, present, and future of disease-modifying therapies for Alzheimer’s disease
Suzuki, K., Iwata, A., & Iwatsubo, T. (2017) · Proceedings of the Japan Academy Series B · doi:10.2183/pjab.93.048 · Cited by 42 · see citing works
Further understanding of tau phosphorylation: implications for therapy
Medina, M., & Avila, J. (2015) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.2015.1000864 · Cited by 41 · see citing works
“Further studies have supported this strategy by administering the peptide incorporated into liposomes in various animal models [76]; a mixture of different tau phospho-peptides to transgenic mice overexpressing a double mutant human tau protein [77]; or a pathological peptide containing pSer422 into Thy-Tau22 transgen…”
BackgroundEarly investigational drugs targeting tau protein for the treatment of Alzheimer’s disease
Anand, K., & Sabbagh, M. N. (2015) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2015.1075002 · Cited by 41 · see citing works
“The vaccine also demonstrated safety with regard to decreased markers of inflammation as measured by immunohistochemistry for astrocytes, microglial activation, immunoglobulin levels, and the number of CD45 T- and B-cells [8].”
BackgroundAnnadurai, N., Sanctis, J. B. D., Hajdúch, M., & Das, V. (2021) · Experimental Neurology · doi:10.1016/j.expneurol.2021.113756 · Cited by 41 · see citing works
Invited review: Drug development for tauopathies
Grüninger, F. (2014) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12192 · Cited by 40 · see citing works
“…Tau 393–408 (pS396/pS404) Reduction in tau pathology Bi et al., 2011 [169] Tau 395–406 (pS396/pS404) Reduction in tau pathology, functional improvement Theunis et al., 2013 [23] Tau 195–231 (pS202/pT205), Tau 207–220 (pS212/pS214), Tau 224–238 (pS231) Reduction in tau pathology Boimel et al., 2010…”
BackgroundLiu, N., Liang, X., Chen, Y., & Xie, L. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102199 · Cited by 41 · see citing works
Vandermeeren, M., Borgers, M., Kolen, K. V., Theunis, C., Vasconcelos, B., Bottelbergs, A., Wintmolders, C., Daneels, G., Willems, R., Dockx, K., et al. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-180404 · Cited by 39 · see citing works
“Several studies have shown beneficial effects of both immunization approaches in transgenic mouse models of tauopa-thy [15–17] but it is not clear which epitope in tau is most suited to target seeding.”
Self-citation
- Authors
- Theunis, C., Crespo-Biel, N., Gafner, V., Pihlgren, M., López-Deber, M. P., Reis, P., Hickman, D. T., Adolfsson, O., Chuard, N., Ndao, D. M., Borghgraef, P., Devijver, H., Van Leuven, F., Pfeifer, A., & Muhs, A.
- Affiliations
- KU Leuven (BE)
- AC Immune (Switzerland) (CH)
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-08-19
- Volume
- 8
- Issue
- 8
- Pages
- e72301
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3747157
- OpenAlex
- W2090968981
- Cited by
- 259
- References
- 78
- Citations by year
- 2026: 9 · 2025: 16 · 2024: 25 · 2023: 17 · 2022: 22 · 2021: 23 · 2020: 25 · 2019: 23 · 2018: 27 · 2017: 22 · 2016: 19 · 2015: 13 · 2014: 16 · 2013: 1
- FWCI
- 11.37
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tau protein, tau immunotherapy, tauopathy, Alzheimer's disease, vaccine safety, neuroinflammation, tau aggregation
- MeSH terms
- Animals, Brain, Disease Models, Animal, Humans, Liposomes, Mice, Transgenic, Peptides, Phosphoproteins, Phosphorylation, Psychomotor Performance, Vaccination, tau Proteins, Treatment Outcome, Alzheimer Vaccines, Tauopathies, Mice, Antibodies, Neutralizing
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