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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 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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“…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
Ceyzériat, K., Zilli, T., Millet, P., Frisoni, G. B., Garibotto, V., & Tournier, B. B. (2020) · Current Alzheimer Research · doi:10.2174/1567205017666200304085513 · Cited by 55
Morató, X., Pytel, V., Jofresa, S., Ruiz, A., & Boada, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23169305 · Cited by 53
“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 56
“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 52
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
“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
Rajamohamedsait, H., Rasool, S., Rajamohamedsait, W., Lin, Y., & Sigurdsson, E. M. (2017) · Scientific Reports · doi:10.1038/s41598-017-17313-1 · Cited by 49
NAKAI, T., Yamada, K., & Mizoguchi, H. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115549 · Cited by 53
“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 60
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 55
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 49
Rosenberg, R. N., Fu, M., & Lambracht‐Washington, D. (2018) · Alzheimer s Research & Therapy · doi:10.1186/s13195-018-0441-4 · Cited by 50
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
Disentangling tau: One protein, many therapeutic approaches
Lane‐Donovan, C., & Boxer, A. L. (2024) · Neurotherapeutics · doi:10.1016/j.neurot.2024.e00321 · Cited by 49
Katsinelos, T., Tuck, B. J., Mukadam, A. S., & McEwan, W. A. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01139 · Cited by 46
“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 46
“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 46
“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 46
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 44
“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 50
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
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
“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
“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
Invited review: Drug development for tauopathies
Grüninger, F. (2014) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12192 · Cited by 40
“…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 44
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 40
“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
Metadata
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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