Ten Years of Tau-Targeted Immunotherapy: The Path Walked and the Roads Ahead

Novak, Petr; Kontsekova, Eva; Zilka, Norbert; Novak, Michal

doi:10.3389/fnins.2018.00798

Cited by 91Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Ten Years of Tau-Targeted Immunotherapy: The Path Walked and the Roads Ahead

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Novak, Petr, Kontsekova, Eva, Zilka, Norbert, Novak, Michal·2018·Frontiers in Neuroscience

DOI 10.3389/fnins.2018.00798PMC PMC6224648

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Abstract

Neurofibrillary pathology comprised of pathological tau protein is closely tied to a range of neurodegenerative disorders, the most common of which is Alzheimer's disease. While they are individually rarer, a range of other disorders, the tauopathies (including Pick's disease, progressive supranuclear palsy, corticobasal degeneration, primary progressive aphasia, and ∼50% of behavioral variant frontotemporal dementia cases) display pronounced underlying tau pathology. In all cases, the distribution and amount of tau pathology closely correlates with the severity and phenotype of cognitive impairment, and with the pattern and degree of brain atrophy. Successfully counteracting tau pathology is likely to halt or slow the progression of these debilitating disorders. This makes tau a target of prime importance, yet an elusive one. The diversity of the tau proteome and post-translational modifications, as well as pathophysiology of tau are reviewed. Beginning 2013, a range of tau-targeted immunotherapies have entered clinical development; these therapies, and their common themes and differences are reviewed. The manuscript provides an extensive discussion on epitope selection for immunotherapies against tau pathology, on immunological mechanisms involved in their action, and challenges such as immune senescence, vaccine design, or evolution of epitopes. Furthermore, we provide methodological recommendations for the characterization of active vaccines and antibodies, animal models, and the target itself - the diseased tau proteome.

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TRx0237 failed to be an add-on treatment for Alzheimer disease.
“The report of this trial revealed that TRx0237 failed to be an add-on treatment for AD [68].”
From Clinical trials of new drugs for Alzheimer disease (2020) · cites this paper as [68]
The Results of Human Clinical Trials section discusses AADvac1, not TRx0237. Searches for TRx0237 and for an adjunctive tau-aggregation treatment found no passage in our copy addressing whether TRx0237 failed as an add-on treatment for Alzheimer’s disease. (LLM, conf=0.76)
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Background
Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase 1 trial
Novák, P., Schmidt, R., Kontseková, E., Žilka, N., Kováčech, B., Škrabana, R., Kazmerova, Z., Katina, S., Fialová, Ľ., Prčina, M., et al. (2016) · The Lancet Neurology · doi:10.1016/s1474-4422(16)30331-3 · Cited by 306 · cited 4× · see citing works
“This diversity in response could, to an extent, be explained by differences in lymphocyte counts, T-helper cells counts, and the percentage off lymphocytes and neutrophil granulocytes (Novak et al., 2017).”
BackgroundInfluential
Frontotemporal dementia
Warren, J. D., Rohrer, J. D., & Rossor, M. N. (2013) · BMJ · doi:10.1136/bmj.f4827 · Cited by 292 · see citing works
Entorhinal Tau Pathology, Episodic Memory Decline, and Neurodegeneration in Aging
Maaß, A., Lockhart, S. N., Harrison, T. M., Bell, R. K., Mellinger, T. J., Swinnerton, K. N., Baker, S. L., Rabinovici, G. D., & Jagust, W. J. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.2028-17.2017 · Cited by 288 · cited 1× · see citing works
“Interestingly, tau pathology in the medial temporal lobe is associated with episodic memory performance and atrophy also in cognitively normal adults, independent of Aβ (Maass et al., 2018).”
Background
A Comprehensive Behavioral Test Battery to Assess Learning and Memory in 129S6/Tg2576 Mice
Wolf, A., Bauer, B., Abner, E. L., Ashkenazy-Frolinger, T., & Hartz, A. M. S. (2016) · PLOS ONE · doi:10.1371/journal.pone.0147733 · Cited by 281 · see citing works
The genetics and neuropathology of frontotemporal lobar degeneration
Sieben, A., Van Langenhove, T., Engelborghs, S., Martin, J.-J., Boon, P., Cras, P., De Deyn, P.-P., Santens, P., Van Broeckhoven, C., & Cruts, M. (2012) · Acta Neuropathologica · doi:10.1007/s00401-012-1029-x · Cited by 280 · cited 1× · see citing works
“gray matter and brainstem (monoaminergic nuclei) Language, behavior, executive function (as bvFTD or PPA) Pathology: (Sieben et al., 2012) Clinics: (Hodges et al.”
Background
Dendritic Tau in Alzheimer’s Disease
Ittner, A., & Ittner, L. M. (2018) · Neuron · doi:10.1016/j.neuron.2018.06.003 · Cited by 278 · cited 4× · see citing works
“In comparison to immunotherapies targeting extracellular pathology, such as Aβ, tau-targeted immunotherapy faces an additional challenge: many types of tau are located intracellularly [whether axonal, dendritic (Ittner and Ittner, 2018), somatic, or nuclear (Paholikova et al.”
BackgroundInfluential
Protein carriers of conjugate vaccines: Characteristics, development and clinical trials
Pichichero, M. E. (2013) · Human Vaccines & Immunotherapeutics · doi:10.4161/hv.26109 · Cited by 263 · cited 2× · see citing works
“, tetanus toxoid (Pichichero, 2013), or artificial carriers that feature a broad spectrum of T-cell epitopes from various antigens (Davtyan et al.”
Background
Efficacy and Safety of A Liposome-Based Vaccine against Protein Tau, Assessed in Tau.P301L Mice That Model Tauopathy
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., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0072301 · Cited by 259 · cited 12× · 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…”
BackgroundInfluential
The human side of microglia
Smith, A. M., & Dragunow, M. (2014) · Trends in Neurosciences · doi:10.1016/j.tins.2013.12.001 · Cited by 256 · cited 1× · see citing works
“They are fundamentally different entities (Smith and Dragunow, 2014); microglia that produce neurotoxic inflammatory mediators in culture may behave in a different manner in the living brain.”
Background
Truncated tau from sporadic Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo
Žilka, N., Filipčík, P., Koson, P., Fialová, Ľ., Škrabana, R., Žilková, M., Rolkova, G., Kontseková, E., & Novák, M. (2006) · FEBS Letters · doi:10.1016/j.febslet.2006.05.029 · Cited by 252 · cited 1× · see citing works
“, 1988), destabilizes microtubules (Zilka et al., 2006), damages the proteasome (Opattova et al.”
Background
Process Outgrowth of Oligodendrocytes Is Promoted by Interaction of Fyn Kinase with the Cytoskeletal Protein Tau
Klein, C., Krämer, E.-M., Cardine, A.-M., Schraven, B., Brandt, R., & Trotter, J. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-03-00698.2002 · Cited by 250 · cited 10× · see citing works
“Treatment of SHR72 transgenic rats with AADvac1 resulted in ∼70% less insoluble tau accumulation in their brains; interestingly, the amount of pathologically hyperphosphorylated tau was reduced by 90-98% (Kontsekova et al., 2014a).”
BackgroundInfluential
First-in-man tau vaccine targeting structural determinants essential for pathological tau–tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer’s disease model
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
Age-related distribution of neuropathologic changes in the cerebral cortex of patients with Down's syndrome. Quantitative regional analysis and comparison with Alzheimer's disease.
Hof, P., Bouras, C., Perl, D. P., Sparks, D., Mehta, N. A., & Morrison, J. H. (1995) · Archives of Neurology · doi:10.1001/archneur.1995.00540280065020 · Cited by 237 · cited 6× · see citing works
“Vertical supranuclear gaze palsy, postural instability, falls, pseudobulbar palsy, rigidity, akinesia; behavior, executive function, and language impaired; Parkinsonism Pathology: (Josephs et al., 2011) Clinics: (Levin et al., 2016; Respondek and Hoglinger, 2016) Tangle-only dementia Neurofibrillary tangles Neuropil t…”
BackgroundInfluential
Human secreted tau increases amyloid-beta production
Bright, J., Hussain, S., Dang, V., Wright, S., Cooper, B., Byun, T., Ramos, C., Singh, A., Parry, G., Stagliano, N., et al. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.09.007 · Cited by 230 · see citing works
Nitration of Tau Protein Is Linked to Neurodegeneration in Tauopathies
Horiguchi, T., Uryu, K., Giasson, B. I., Ischiropoulos, H., Lightfoot, R. T., Bellmann, C., Richter‐Landsberg, C., Lee, V. M. ‐., & Trojanowski, J. Q. (2003) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63462-1 · Cited by 220 · cited 1× · see citing works
“, 1993), nitration (Horiguchi et al., 2003), glycation (Ledesma et al.”
The Differential Diagnosis and Treatment of Atypical Parkinsonism
Levin, J., Kurz, A., Arzberger, T., Giese, A., & Höglinger, G. U. (2016) · Deutsches Ärzteblatt international · doi:10.3238/arztebl.2016.0061 · Cited by 214 · see citing works
Axonal degeneration in Alzheimer's disease: When signaling abnormalities meet the axonal transport system
Kanaan, N. M., Pigino, G. F., Brady, S. T., Lazarov, O., Binder, L. I., & Morfini, G. A. (2012) · Experimental Neurology · doi:10.1016/j.expneurol.2012.06.003 · Cited by 208 · see citing works
Tau deletion promotes brain insulin resistance
Marciniak, E., Leboucher, A., Caron, E., Ahmed, T., Tailleux, A., Dumont, J., Issad, T., Gerhardt, E., Pagesy, P., Vileno, M., et al. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20161731 · Cited by 205 · cited 1× · see citing works
“Reducing healthy tau protein was found to have detrimental effects (Marciniak et al., 2017), and (presumably) diluting the effect of the antibody between healthy (irrelevant) and pathological tau forms could reduce the overall efficacy of the treatment.”
Background
Extracellular Monomeric and Aggregated Tau Efficiently Enter Human Neurons through Overlapping but Distinct Pathways
Evans, L., Wassmer, T., Fraser, G. M., Smith, J. C., Perkinton, M. S., Billinton, A., & Livesey, F. J. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.03.021 · Cited by 187 · cited 3× · see citing works
“The final answer to this question is especially relevant for tau-targeted immunotherapies that don’t preferentially target diseased tau, as undesired interference with interneuronal transfer of non-pathogenic tau may have profound consequences (Bright et al., 2015; Evans et al., 2018).”
BackgroundInfluential
Abnormal Tau-Containing Filaments in Neurodegenerative Diseases
Crowther, R. A., & Goedert, M. (2000) · Journal of Structural Biology · doi:10.1006/jsbi.2000.4270 · Cited by 185 · see citing works
Anti‐tau antibody reduces insoluble tau and decreases brain atrophy
Yanamandra, K., Jiang, H., Mahan, T. E., Maloney, S. E., Wozniak, D. F., Diamond, M. I., & Holtzman, D. M. (2015) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.176 · Cited by 185 · cited 2× · see citing works
“Improvements in sensorimotor function were also seen (Yanamandra et al., 2015).”
Background
Pathological Tau Disrupts Ongoing Network Activity
Menkes-Caspi, N., Yamin, H. G., Kellner, V., Spires-Jones, T. L., Cohen, D., & Stern, E. A. (2015) · Neuron · doi:10.1016/j.neuron.2015.01.025 · Cited by 184 · see citing works
Developmental regulation of tau phosphorylation, tau kinases, and tau phosphatases
Yu, Y., Run, X., Liang, Z., Li, Y., Liu, F., Liu, Y. M., Iqbal, K., Grundke, I., & Gong, C. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.05882.x · Cited by 177 · see citing works
A comparative study of histological and immunohistochemical methods for neurofibrillary tangles and senile plaques in Alzheimer's disease
Vallet, P. G., Guntern, R., Hof, P. R., Golaz, J., Delacourte, A., Robakis, N. K. R. K., & Bouras, C. (1992) · Acta Neuropathologica · doi:10.1007/bf00308476 · Cited by 170 · see citing works
Two Novel Tau Antibodies Targeting the 396/404 Region Are Primarily Taken Up by Neurons and Reduce Tau Protein Pathology
Gu, J., Congdon, E. E., & Sigurdsson, E. M. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.494922 · Cited by 163 · cited 1× · see citing works
“One group reports this is the case (Gu et al., 2013), while numerous others don’t report any passage of antibodies into neurons.”
Background
Vulnerability of cortical neurons to Alzheimer's and Parkinson's diseases
Braak, H., Rüb, U., Schultz, C., & Tredici, K. D. (2006) · Journal of Alzheimer s Disease · doi:10.3233/jad-2006-9s305 · Cited by 163 · see citing works
Neurofibrillary tangle-predominant dementia: comparison with classical Alzheimer disease
Jellinger, K. A., & Attems, J. (2006) · Acta Neuropathologica · doi:10.1007/s00401-006-0156-7 · Cited by 157 · see citing works
Perforant path synaptic loss correlates with cognitive impairment and Alzheimer’s disease in the oldest-old
Robinson, J. L., Molina-Porcel, L., Corrada, M. M., Raible, K., Lee, E. B., Lee, V. M.-Y., Kawas, C. H., & Trojanowski, J. Q. (2014) · Brain · doi:10.1093/brain/awu190 · Cited by 157 · see citing works
Neurons associated with aggrecan-based perineuronal nets are protected against tau pathology in subcortical regions in Alzheimer's disease
Morawski, M., Brückner, G., Jäger, C., Seeger, G., & Arendt, T. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.05.022 · Cited by 156 · cited 2× · see citing works
“, 2006), hinting at a selective vulnerability of flexible, poorly myelinated neurons with limited perineuronal support nets (Morawski et al., 2010) to AD pathology.”
Background
The role of Fc–FcγR interactions in IgG-mediated microbial neutralization
Bournazos, S., DiLillo, D. J., & Ravetch, J. V. (2015) · The Journal of Experimental Medicine · doi:10.1084/jem.20151267 · Cited by 154 · cited 1× · see citing works
“Via their effector functions, antibodies are able to engage immune cells, such as microglia, to phagocyte and degrade pathological tau (Bournazos et al., 2015).”
Background
Tau Kinetics in Neurons and the Human Central Nervous System
Sato, C., Barthélemy, N. R., Mawuenyega, K. G., Patterson, B. W., Gordon, B. A., Jockel-Balsarotti, J., Sullivan, M., Crisp, M. J., Kasten, T., Kirmess, K. M., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.04.035 · Cited by 154 · cited 6× · see citing works
“Furthermore, the function of tau differs based on the molecule’s location – axonal (Méphon-Gaspard et al., 2016), dendritic (Ittner and Ittner, 2018), nuclear (Paholikova et al., 2014), or extraneuronal (Yamada et al., 2014; Sato et al., 2018).”
BackgroundInfluential
Advances in Therapeutic Fc Engineering – Modulation of IgG-Associated Effector Functions and Serum Half-life
Saxena, A., & Wu, D. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00580 · Cited by 150 · cited 1× · see citing works
“As a trade-off, this isotype promotes complement activation the most; should this trait be undesirable, there are ways to mitigate it (Saxena and Wu, 2016).”
Background
Senile Dementia with Tangles (Tangle Predominant Form of Senile Dementia)
Jellinger, K. A., & Bancher, C. (1998) · Brain Pathology · doi:10.1111/j.1750-3639.1998.tb00160.x · Cited by 148 · see citing works
Normal human immunoglobulin G4 is bispecific: it has two different antigen‐combining sites
Schuurman, J., van Ree, R., Perdok, G. J., van Doorn, H. R., Tan, K. Y., & Aalberse, R. C. (1999) · Immunology · doi:10.1046/j.1365-2567.1999.00845.x · Cited by 148 · cited 1× · see citing works
“As for IgG4, one fact which must be kept in mind is that monovalent bispecific antibodies will result from the IgG4 Fab arm exchange (Schuurman et al., 1999), consisting of one light and one heavy chain of a random endogenous IgG4 antibody, and one half of the administered IgG4 monoclonal.”
Background
Who fans the flames of Alzheimer's disease brains? Misfolded tau on the crossroad of neurodegenerative and inflammatory pathways
Žilka, N., Kazmerova, Z., Jadhav, S., Neradil, P., Maďari, A., Obetkova, D., Bugos, O., & Novák, M. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-47 · Cited by 147 · see citing works
Tau protein is essential for stress-induced brain pathology
Lopes, S., Vaz‐Silva, J., Pinto, V., Dalla, C., Kokras, N., Bedenk, B. T., Mack, N., Czisch, M., Almeida, O. F. X., Sousa, N., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1600953113 · Cited by 147 · cited 1× · see citing works
“For example, psychological stress and stress-induced kinases were shown to increase the phosphorylation burden of tau (Rissman et al., 2012; Lopes et al., 2016).”
Background
FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer's disease
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 · cited 2× · see citing works
“The same was seen in histological assessment, where patient sera were able to stain tau pathology in brains with Alzheimer’s disease, corticobasal degeneration, progressive supranuclear palsy, and Pick’s disease, highlighting the fact that the targeted conformational epitopes in the microtubule-binding region of tau r…”
Background
The Core of Tau-Paired Helical Filaments Studied by Scanning Transmission Electron Microscopy and Limited Proteolysis
von Bergen�, M., Barghorn, S., Müller, S. A., Pickhardt, M., Biernat, J., Mandelkow, E., Davies, P., Aebi, U., & Mandelkow�, E. (2006) · Biochemistry · doi:10.1021/bi052530j · Cited by 141 · see citing works
Survival Analysis I: The Kaplan-Meier Method
Stel, V. S., Dekker, F. W., Tripepi, G. L., Zoccali, C., & Jager, K. J. (2011) · Nephron Clinical Practice · doi:10.1159/000324758 · Cited by 140 · see citing works
Tau Structures
Avila, J., Jiménez, J. S., Sayas, C. L., Bolós, M., Zabala, J. C., Rivas, G., & Hernández, F. (2016) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2016.00262 · Cited by 140 · see citing works
Preclinical and Clinical Development of ABBV-8E12, a Humanized Anti-Tau Antibody, for Treatment of Alzheimer's Disease and Other Tauopathies.
West, T., Hu, Y., Verghese, P. B., Bateman, R. J., Braunstein, J. B., Fogelman, I., Budur, K., Florian, H., Mendonca, N., & Holtzman, D. M. (2017) · PubMed · doi:10.14283/jpad.2017.36 · Cited by 132 · cited 1× · see citing works
“ABBV 8E12 targets aa25-30 at the N-terminus of tau with the aim to clear extracellular forms, and thus inhibit seeding (West et al., 2017).”
Background
Epitope determines efficacy of therapeutic anti-Tau antibodies in a functional assay with human Alzheimer Tau
Courade, J., Angers, R. C., Mairet‐Coello, G., Pacico, N., Tyson, K. L., Lightwood, D. J., Munro, R., McMillan, D., Griffin, R., BAKER, T. S., et al. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1911-2 · Cited by 131 · see citing works
Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)
Wszolek, Z. K., Tsuboi, Y., Ghetti, B., Pickering-Brown, S., Baba, Y., & Cheshire, W. P. (2006) · Orphanet Journal of Rare Diseases · doi:10.1186/1750-1172-1-30 · Cited by 128 · see citing works
Antibody-Mediated Targeting of Tau In Vivo Does Not Require Effector Function and Microglial Engagement
Lee, S.-H., Le Pichon, C. E., Adolfsson, O., Gafner, V., Pihlgren, M., Lin, H., Solanoy, H., Brendza, R., Ngu, H., Foreman, O., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.06.099 · Cited by 125 · see citing works
Relevance of Phosphorylation and Truncation of Tau to the Etiopathogenesis of Alzheimer’s Disease
Zhou, Y., Shi, J., Chu, D., Hu, W. H., Guan, Z., Gong, C., Iqbal, K., & Liu, F. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00027 · Cited by 123 · cited 1× · see citing works
“On the other hand, one or both termini of tau are absent in an important subset of pathological tau forms in the AD brain (Zilka et al., 2012b; Zhou et al., 2018), which thus escape immunotherapies aimed at epitopes on termini.”
Background
Harmonized diagnostic criteria for Alzheimer's disease: recommendations
Morris, J. C., Blennow, K., Froelich, L., Nordberg, A. K., Soininen, H. S., Waldemar, G., Wahlund, L., & Dubois, B. (2014) · Journal of Internal Medicine · doi:10.1111/joim.12199 · Cited by 120 · see citing works
Tau Antibody Targeting Pathological Species Blocks Neuronal Uptake and Interneuron Propagation of Tau in Vitro
Nobuhara, C. K., DeVos, S. L., Commins, C., Wegmann, S., Moore, B. D., Roe, A. D., Costantino, I., Frosch, M. P., Pitstick, R., Carlson, G. A., et al. (2017) · The American Journal of Pathology · doi:10.1016/j.ajpath.2017.01.022 · Cited by 120 · cited 1× · see citing works
“Various seeding and tau spreading assays can be utilized to evaluate the antibody’s capability to halt the spread of tauons (Nobuhara et al., 2017).”
Background
Identification of structural determinants on tau protein essential for its pathological function: novel therapeutic target for tau immunotherapy in Alzheimer’s disease
Kontsekova, E., Zilka, N., Kovacech, B., Skrabana, R., & Novak, M. (2014) · Alzheimer's Research & Therapy · doi:10.1186/alzrt277 · Cited by 112 · see citing works
Corticotropin-releasing factor receptor-dependent effects of repeated stress on tau phosphorylation, solubility, and aggregation
Rissman, R. A., Staup, M. A., Lee, A. R., Justice, N. J., Rice, K. C., Vale, W., & Sawchenko, P. E. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1203140109 · Cited by 97 · cited 1× · see citing works
“For example, psychological stress and stress-induced kinases were shown to increase the phosphorylation burden of tau (Rissman et al., 2012; Lopes et al., 2016).”
Background
Two motifs within the tau microtubule‐binding domain mediate its association with the hsc70 molecular chaperone
Sarkar, M., Kuret, J., & Lee, G. S. (2008) · Journal of Neuroscience Research · doi:10.1002/jnr.21721 · Cited by 96 · cited 1× · see citing works
“The pathological conformation of tau molecules may be changed as antibodies bind them (another form of templatemediated conformational change, with the antibody acting as template/chaperone) (Sarkar et al., 2008).”
Background
Argyrophilic Grain Disease: Demographics, Clinical, and Neuropathological Features From a Large Autopsy Study
Rodriguez, R. D., Suemoto, C. K., Molina, M., Nascimento, C. F., Leite, R. E. P., Ferretti‐Rebustini, R. E. D. L., Farfel, J. M., Heinsen, H., Nitríni, R., Uéda, K., et al. (2016) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlw034 · Cited by 94 · see citing works
Tau pathology involves protein phosphatase 2A in Parkinsonism-dementia of Guam
Arif, M., Kazim, S. F., Grundke, I., Garruto, R. M., & Iqbal, K. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1322614111 · Cited by 91 · cited 3× · see citing works
“Numerous less well known and less common disorders with tau lesions other than those mentioned in Table 1 exist, e.g., familial British dementia and familial Danish dementia (Vidal et al., 1999), Parkinsonism-dementia complex of Guam (Arif et al., 2014), and many others (Spillantini and Goedert, 2013).”
Background
The phenotypic spectrum of progressive supranuclear palsy
Respondek, G., & Höglinger, G. U. (2015) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2015.09.041 · Cited by 90 · see citing works
Microglia communication: parallels between aging and Alzheimer's disease
Udeochu, J. C., Shea, J. M., & Villeda, S. A. (2016) · Clinical and Experimental Neuroimmunology · doi:10.1111/cen3.12307 · Cited by 87 · see citing works
Human CNS immune senescence and neurodegeneration
Streit, W. J., & Xue, Q.-S. (2014) · Current Opinion in Immunology · doi:10.1016/j.coi.2014.05.005 · Cited by 86 · see citing works
Age-Related Changes of Adaptive and Neuropsychological Features in Persons with Down Syndrome
Ghezzo, A., Salvioli, S., Solimando, M. C., Palmieri, A., Chiostergi, C., Scurti, M., Lomartire, L., Bedetti, F., Cocchi, G., Follo, D., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0113111 · Cited by 86 · see citing works
Starvation and inhibition of lysosomal function increased tau secretion by primary cortical neurons
Mohamed, N., Plouffe, V., Rémillard‐Labrosse, G., Planel, E., & Leclerc, N. M. (2014) · Scientific Reports · doi:10.1038/srep05715 · Cited by 86 · cited 1× · see citing works
“Also, we suspect that neurons outsource a portion of tau to their supporting cells for processing (Morawski et al., 2010; Mohamed et al., 2014); this tau could also be targeted in the extracellular space.”
Background
First transgenic rat model developing progressive cortical neurofibrillary tangles
Filipčík, P., Žilka, N., Bugos, O., Kučerák, J., Koson, P., Novák, P., & Novák, M. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.10.015 · Cited by 84 · see citing works
An experimental rat model of sporadic Alzheimer’s disease and rescue of cognitive impairment with a neurotrophic peptide
Bolognin, S., Blanchard, J., Wang, X., Basurto‐Islas, G., Tung, Y. C., Kohlbrenner, E., Grundke, I., & Iqbal, K. (2011) · Acta Neuropathologica · doi:10.1007/s00401-011-0908-x · Cited by 77 · see citing works
Truncated tau expression levels determine life span of a rat model of tauopathy without causing neuronal loss or correlating with terminal neurofibrillary tangle load
Koson, P., Žilka, N., Kováč, A., Kováčech, B., Korenova, M., Filipčík, P., & Novák, M. (2008) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2008.06329.x · Cited by 75 · see citing works
Misfolded Truncated Protein τ Induces Innate Immune Response via MAPK Pathway
Kovac, A., Zilka, N., Kazmerova, Z., Cente, M., Zilkova, M., & Novak, M. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1100216 · Cited by 75 · cited 1× · see citing works
“…of synaptic markers Robinson et al., 2014 Neuroinflammation Activation of astrocytes and microglia, cytokine profile Stozicka et al., 2010; Kovac et al., 2011; Zilka et al., 2012a; Heneka et al., 2015; Frontiers in Neuroscience | www.frontiersin.org 5 November 2018 | Volume 12 | Article…”
Background
High–Molecular-Weight Paired Helical Filaments from Alzheimer Brain Induces Seeding of Wild-Type Mouse Tau into an Argyrophilic 4R Tau Pathology in Vivo
Audouard, E., Houben, S., Masaracchia, C., Yilmaz, Z., Suain, V., Authelet, M., Decker, R. D., Buée, L., Boom, A., Leroy, K., et al. (2016) · American Journal Of Pathology · doi:10.1016/j.ajpath.2016.06.008 · Cited by 68 · cited 1× · see citing works
“…Staining with Thioflavin-S, Congo-red, silver Vallet et al., 1992 Seeding capability In vitro (solution, cell assays) and in vivo (stereotaxic) seeding Audouard et al., 2016; Courade et al., 2018 Transgene expression level Quantitative real time PCR (mRNA), Western blot, ELISA (protein),…”
Background
A fresh perspective from immunologists and vaccine researchers: Active vaccination strategies to prevent and reverse Alzheimer's disease
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
Variation in tau isoform expression in different brain regions and disease states
Majounie, E., Cross, W. C. H., Newsway, V., Dillman, A., Vandrovcová, J., Morris, C. M., Nalls, M. A., Ferrucci, L., Owen, M. J., O’Donovan, M. C., et al. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.01.017 · Cited by 65 · cited 1× · see citing works
“For example, brain regions predominantly affected by the 4R-tauopathy PSP express a higher ratio of 4R-tau even in healthy controls (Majounie et al., 2013).”
Background
Transition of Tau Protein from Disordered to Misordered in Alzheimer’s Disease
Kovačech, B., Škrabana, R., & Novák, M. (2010) · Neurodegenerative Diseases · doi:10.1159/000283478 · Cited by 51 · see citing works
N-terminal Truncation of Microtubule Associated Protein Tau Dysregulates its Cellular Localization
Paholikova, K., Šalingová, B., Opattová, A., Škrabana, R., Majerová, P., Žilka, N., Kováčech, B., Žilková, M., Baráth, P., & Novák, M. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-140996 · Cited by 50 · cited 2× · see citing works
“, 2016), dendritic (Ittner and Ittner, 2018), nuclear (Paholikova et al., 2014), or extraneuronal (Yamada et al.”
Background
The self-perpetuating tau truncation circle
Žilka, N., Kováčech, B., Baráth, P., Kontseková, E., & Novák, M. (2012) · Biochemical Society Transactions · doi:10.1042/bst20120015 · Cited by 50 · cited 3× · see citing works
“It is well known that truncation of tau’s N- and C-terminus promotes the molecule’s transition from its healthy state into pathological forms (Zilka et al., 2012b).”
Background
Genetic background modifies neurodegeneration and neuroinflammation driven by misfolded human tau protein in rat model of tauopathy: implication for immunomodulatory approach to Alzheimer's disease
Stožická, Z., Žilka, N., Novák, P., Kováčech, B., Bugos, O., & Novák, M. (2010) · Journal of Neuroinflammation · doi:10.1186/1742-2094-7-64 · Cited by 44 · see citing works
Characterization of paired helical filaments by scanning transmission electron microscopy
Ksiȩżak-Reding, H., & Wall, J. S. (2005) · Microscopy Research and Technique · doi:10.1002/jemt.20188 · Cited by 42 · see citing works
Role of tau in the spatial organization of axonal microtubules: keeping parallel microtubules evenly distributed despite macromolecular crowding
Méphon-Gaspard, A., Boca, M., Pioche‐Durieu, C., Desforges, B., Burgo, A., Hamon, L., Piétrement, O., & Pastré, D. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2216-z · Cited by 42 · cited 1× · see citing works
“Furthermore, the function of tau differs based on the molecule’s location – axonal (Méphon-Gaspard et al., 2016), dendritic (Ittner and Ittner, 2018), nuclear (Paholikova et al.”
Background
Intracellular Degradation of Misfolded Tau Protein Induced by Geldanamycin is Associated with Activation of Proteasome
Opattová, A., Filipčík, P., Cente, M., & Novák, M. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-121072 · Cited by 40 · cited 1× · see citing works
“, 2006), damages the proteasome (Opattova et al., 2013), causes neuronal and synaptic loss (Gómez-Isla et al.”
Background
Tau Conformation as a Target for Disease-Modifying Therapy: The Role of Truncation
Novák, P., Cehlár, O., Škrabana, R., & Novák, M. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-179942 · Cited by 36 · cited 3× · see citing works
“Conformation is an often-overlooked aspect of tau pathology (Novak et al., 2018b).”
BackgroundInfluential
NeuroScale, the battery of behavioral tests with novel scoring system for phenotyping of transgenic rat model of tauopathy
Korenova, M., Žilka, N., Stožická, Z., Bugos, O., Vanický, I., & Novák, M. (2008) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2008.09.027 · Cited by 36 · see citing works
Tauons and Prions: Infamous Cousins?
Novák, P., Prčina, M., & Kontseková, E. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-110194 · Cited by 35 · see citing works
Argyrophilic grain disease: An update on a frequent cause of dementia
Grinberg, L. T., & Heinsen, H. (2009) · Dementia & Neuropsychologia · doi:10.1590/s1980-57642009dn30100002 · Cited by 30 · cited 1× · see citing works
“Pathology: (Grinberg and Heinsen, 2009) Clinics:(Rodriguez et al., 2016) Chronic traumatic encephalopathy Neurofibrillary tangles and neurites, astrocytic tangles 3R+4R tau Focal (perivascular) epicenters, amygdala, hippocampus, nucleus basalis of Meynert, substantia nigra, locus coeruleus Mainly…”
Background
MultiTEP platform-based DNA epitope vaccine targeting N-terminus of tau induces strong immune responses and reduces tau pathology in THY-Tau22 mice
Davtyan, H., Chen, W. W., Zagorski, K., Davis, J., Petrushina, I., Kazarian, K., Cribbs, D. H., Agadjanyan, M. G., Blurton-Jones, M., & Ghochikyan, A. (2017) · Vaccine · doi:10.1016/j.vaccine.2017.03.020 · Cited by 30 · see citing works
Differences in structure and function between human and murine tau
Hernández, F., Cuadros, R., Ollà, I., García, C., Ferrer, I., Perry, G. L., & Ávila, J. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.08.010 · Cited by 23 · cited 1× · see citing works
“While sequence homology between human and rodent tau is high, there are important differences in sequence and function, which may impact whether particular disease mechanisms can be modeled in rodents at all (Hernandez et al., 2018).”
Background
Methods for Measuring Tau Pathology in Transgenic Mouse Models
Forest, S. K., Acker, C. M., d’Abramo, C., & Davies, P. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-121354 · Cited by 22 · see citing works
Fronto-temporal lobar degeneration: neuropathology in 60 cases
Seilhean, D., Ber, I. L., Sarazin, M., Lacomblez, L., Millecamps, S., Salachas, F., Pradat, P., Forestier, N. L., Leguern, É., Dubois, B., et al. (2011) · Journal of Neural Transmission · doi:10.1007/s00702-011-0649-y · Cited by 13 · cited 5× · see citing works
“Vertical supranuclear gaze palsy, postural instability, falls, pseudobulbar palsy, rigidity, akinesia; behavior, executive function, and language impaired; Parkinsonism Pathology: (Josephs et al., 2011) Clinics: (Levin et al., 2016; Respondek and Hoglinger, 2016) Tangle-only dementia Neurofibrillary tangles Neuropil t…”
Influential
Novel Phospho-Tau Monoclonal Antibody Generated Using a Liposomal Vaccine, with Enhanced Recognition of a Conformational Tauopathy Epitope
Theunis, C., Adolfsson, O., Crespo‐Biel, N., Piorkowska, K., Pihlgren, M., Hickman, D. T., Gafner, V., Borghgraef, P., Devijver, H., Pfeifer, A., et al. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160695 · Cited by 11 · see citing works
Challenges in early clinical development of adjuvanted vaccines
Cioppa, G. D., Jónsdóttir, I., & Lewis, D. (2015) · Vaccine · doi:10.1016/j.vaccine.2015.02.031 · Cited by 9 · cited 1× · see citing works
“The phenotype of AD and non-AD tauopathies aligns with the distribution of neurofibrillary lesions, and the severity of impairment is tied to the amount of tau pathology present (Dickson et al., 2011; Josephs et al., 2011; Nelson et al., 2012).”
Background
Neuronal Expression of Truncated Tau Efficiently Promotes Neurodegeneration in Animal Models: Pitfalls of Toxic Oligomer Analysis
Škrabana, R., Kováčech, B., Filipčík, P., Žilka, N., Jadhav, S., Smolek, T., Kontseková, E., & Novák, M. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-161124 · Cited by 7 · cited 1× · see citing works
“Models currently employed by the field are exceedingly diverse, differing in transgene (almost exclusively various forms of mutated tau), genetic background (multiple crossings of various mouse lines generating extensive variability of the phenotype), and expression level (related to the promotor), and thus it is not…”
Background
Untitled work
(1997) · doi:10.1002/(sici)1097-4547(19970415)48:2

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Clinical trials of new drugs for Alzheimer disease
Huang, L.-K., Chao, S.-P., & Hu, C.-J. (2020) · Journal of Biomedical Science · doi:10.1186/s12929-019-0609-7 · Cited by 702 · 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
“95 Tau protein is a microtubule associated protein that is expressed mainly in neurons.”
Background
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
Phosphorylated Tau in Alzheimer’s Disease and Other Tauopathies
Rawat, P., Sehar, U., Bisht, J., Selman, A., Culberson, J., & Reddy, P. H. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232112841 · Cited by 509 · see citing works
“1 vaccine induces specific antibodies aimed at three or four conformational epitopes of tangles to form tau protein with an exposed microtubule-binding repeat domain to prevent spreading, prevent tau aggregation, and promote tau clearance [225].”
Background
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
A 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
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
GSK3β and tau protein in Alzheimer's disease and epilepsy
Toral-Rios, D., Pichardo-Rojas, P. S., Alonso-Vanegas, M., & Campos-Peña, V. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00019 · Cited by 158 · 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
Canine Cognitive Dysfunction and Alzheimer’s Disease – Two Facets of the Same Disease?
Mihevc, S. P., & Majdič, G. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00604 · Cited by 138 · 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
“This produces a lot of variability due to the variable levels of functionality and immunogenicity of the patients’ immune systems in a clinical trial, and therefore produce unreliable results (Novak et al., 2018a) (Fig.”
Background
Tau in neurodegenerative diseases: molecular mechanisms, biomarkers, and therapeutic strategies
Zhang, X., Wang, J., Zhang, Z., & Ye, K. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00429-6 · Cited by 106 · see citing works
“To date, active immunization therapies including AADvac1 (targeting phosphoryla-tion-independent conformational epitope) and ACI-35 (targeting Ser396/Ser404 epitope) are in clinical trials [239–242].”
Background
Immunotherapies 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
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
“Tau-targeted immunotherapy began in 2013 [303], and since then a dozen of different types of immunological strategies were subject of clinical trials, including two active immunizations (vaccines) and humanized monoclonal antibodies directed towards distinct tau epitopes aiming passive immunization (reviewed in Refere…”
Background
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
“It was shown to reach nearly 100% inhibition of fibrillization at an antibody concentration of 300 nM [83].”
Background
Active poly‐GA vaccination prevents microglia activation and motor deficits in a C9orf72 mouse model
Zhou, Q., Mareljic, N., Michaelsen, M., Parhizkar, S., Heindl, S., Nuscher, B., Farny, D., Czuppa, M., Schludi, C., Graf, A., et al. (2019) · EMBO Molecular Medicine · doi:10.15252/emmm.201910919 · Cited by 62 · see citing works
“In contrast to the side effects of Ab vaccination in humans, repeated active immunization with a peptide vaccine targeting Tau showed no adverse events in a phase 1 trials (Novak et al, 2017, 2018b).”
BackgroundMethod
Characterization of tau binding by gosuranemab
Sopko, R., Golonzhka, O., Arndt, J. W., Quan, C., Czerkowicz, J., Cameron, A., Smith, B., Yogapriya, M., Gibbons, G. S., Kim, S., et al. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.105120 · Cited by 64 · see citing works
“As a means to attenuate the transfer of extracellular tau and slow disease progression, a number of tau immunotherapies are under investigation (Colin et al., 2020; Jadhav et al., 2019; Novak et al., 2018; Sigurdsson, 2018).”
Background
Functional Integrity of Synapses in the Central Nervous System of Cognitively Intact Individuals with High Alzheimer’s Disease Neuropathology Is Associated with Absence of Synaptic Tau Oligomers
Singh, A., Allen, D., Fracassi, A., Tumurbaatar, B., Natarajan, C., Scaduto, P., Woltjer, R., Kayed, R., Limon, A., Krishnan, B., et al. (2020) · Journal of Alzheimer's Disease · doi:10.3233/jad-200716 · Cited by 56 · see citing works
Resveratrol Rescues Tau-Induced Cognitive Deficits and Neuropathology in a Mouse Model of Tauopathy
Sun, X., Dong, Q.-X., Zhu, J., Sun, X., Zhang, L., Qiu, M., Yu, X., & Liu, R. (2019) · Current Alzheimer Research · doi:10.2174/1567205016666190801153751 · Cited by 58 · see citing works
Therapeutic antibody targeting microtubule-binding domain prevents neuronal internalization of extracellular tau via masking neuron surface proteoglycans
Weisová, P., Cehlár, O., Škrabana, R., Žilková, M., Filipčík, P., Kováčech, B., Prčina, M., Wojčiaková, Ľ., Fialová, Ľ., Smolek, T., et al. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0770-y · Cited by 52 · 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
The Role of Antibodies and Their Receptors in Protection Against Ordered Protein Assembly in Neurodegeneration
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
“A Phase I trial demonstrated that vaccination successfully induced an anti-tau immune response in 29/30 patients, which was biased toward an IgG1 response (107, 108).”
Background
N-terminal tau truncation in the pathogenesis of Alzheimer's disease (AD): Developing a novel diagnostic and therapeutic approach
Amadoro, G., Latina, V., Corsetti, V., & Calissano, P. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2019.165584 · Cited by 42 · see citing works
Passive immunotherapy for N-truncated tau ameliorates the cognitive deficits in two mouse Alzheimer’s disease models
Corsetti, V., Borreca, A., Latina, V., Giacovazzo, G., Pignataro, A., Krashia, P., Natale, F., Cocco, S., Rinaudo, M., Malerba, F., et al. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa039 · Cited by 41 · see citing works
Passive Immunotherapies Targeting Amyloid Beta and Tau Oligomers in Alzheimer’s Disease
Zanden, C. M. V., & Chi, E. Y. (2019) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2019.10.024 · Cited by 40 · see citing works
Nanoliposomes as a Therapeutic Tool for Alzheimer’s Disease
Ordóñez‐Gutiérrez, L., & Wandosell, F. G. (2020) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2020.00020 · Cited by 40 · see citing works
“Thus, different therapeutic approaches have been proposed, some of which have been deeply studied in several assays (Novak et al., 2018a).”
Background
Novel Therapeutic Strategies in Alzheimer’s Disease: Pitfalls and Challenges of Anti-Amyloid Therapies and Beyond
Tondo, G., Marchi, F. D., Bonardi, F., Menegon, F., Verrini, G., Aprile, D., Anselmi, M., Mazzini, L., & Comi, C. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13113098 · Cited by 43 · see citing works
“In the phase I study, almost all mild-to-moderate AD patients developed a solid anticorpal immune response, without severe adverse events [150].”
Background
Humanized tau antibodies promote tau uptake by human microglia without any increase of inflammation
Žilková, M., Nölle, A., Kováčech, B., Kontseková, E., Weisová, P., Filipčík, P., Škrabana, R., Prčina, M., Hromádka, T., Cehlár, O., et al. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-00948-z · Cited by 35 · see citing works
Systemic delivery of a specific antibody targeting the pathological N-terminal truncated tau peptide reduces retinal degeneration in a mouse model of Alzheimer’s Disease
Latina, V., Giacovazzo, G., Cordella, F., Balzamino, B. O., Micera, A., Varano, M., Marchetti, C., Malerba, F., Florio, R., Ercole, B. B., et al. (2021) · Acta Neuropathologica Communications · doi:10.1186/s40478-021-01138-1 · Cited by 33 · see citing works
Prion-like properties of Tau assemblies
Clavaguera, F., Duyckaerts, C. J., & Haı̈k, S. (2020) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2019.11.022 · Cited by 32 · see citing works
Opportunities and challenges in delivering biologics for Alzheimer’s disease by low-intensity ultrasound
Chen, L., Cruz, E., Oikari, L. E., Padmanabhan, P., Song, J. H., & Götz, J. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2022.114517 · Cited by 34 · see citing works
Functional Selection of Tau Oligomerization‐Inhibiting Aptamers
Wang, B., Pan, X., Teng, I., Li, X., Kobeissy, F. H., Wu, Z., Zhu, J., Cai, G., Yan, H., Yan, X., et al. (2024) · Angewandte Chemie International Edition · doi:10.1002/anie.202402007 · Cited by 29 · see citing works
Active immunization with tau epitope in a mouse model of tauopathy induced strong antibody response together with improvement in short memory and pSer396-tau pathology
Joly‐Amado, A., Davtyan, H., Serraneau, K. S., Jules, P., Zitnyar, A., Pressman, E., Zagorski, K., Antonyan, T., Hovakimyan, A., Paek, H., et al. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104636 · Cited by 29 · see citing works
“reported that a trend towards slower cognitive decline and lower hippocampal atrophy rate was observed in patients with higher antibody titers (Novak et al., 2018).”
Peptide-Based Vaccines for Neurodegenerative Diseases: Recent Endeavors and Future Perspectives
Vassilakopoulou, V., Karachaliou, C., Evangelou, A., Zikos, C. C., & Livaniou, E. (2021) · Vaccines · doi:10.3390/vaccines9111278 · Cited by 26 · see citing works
“ACI-35 is a liposome-based tau-vaccine candidate that contains 16 copies of a synthetic tau phospho-peptide; peptides have been suitably modified, so as to include two palmitic acid chains at each terminus and thus allow assembly into liposomes [14,88].”
BackgroundInfluential
Anti-acetylated-tau immunotherapy is neuroprotective in tauopathy and brain injury
Bravo, C., Krukowski, K., Barker, S., Wang, C., Li, Y., Fan, L., Vázquez‐Rosa, E., Shin, M., Wong, M. Y., McCullough, L. D., et al. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00733-9 · Cited by 25 · see citing works
A MultiTEP platform-based epitope vaccine targeting the phosphatase activating domain (PAD) of tau: therapeutic efficacy in PS19 mice
Hovakimyan, A., Antonyan, T., Shabestari, S. K., Svystun, O., Chailyan, G., Coburn, M., Carlen-Jones, W., Petrushina, I., Chadarevian, J. P., Zagorski, K., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-51809-2 · Cited by 26 · see citing works
Tau Protein-Targeted Therapies in Alzheimer’s Disease: Current State and Future Perspectives
Pluta, R. M., & Ułamek-Kozioł, M. (2020) · Exon Publications eBooks · doi:10.36255/exonpublications.alzheimersdisease.2020.ch4 · Cited by 24 · see citing works
Nanotechnology for tau pathology in Alzheimer's disease
Ma, R., Mu, Q., Xi, Y., Liu, G., & Liu, C. (2024) · Materials Today Bio · doi:10.1016/j.mtbio.2024.101145 · Cited by 23 · see citing works
Nanobiotechnology in Neurodegenerative Diseases
Jampílek, J., Kráľová, K., Novák, P., & Novák, M. (2019) · Springer eBooks · doi:10.1007/978-3-030-30930-5_4 · Cited by 22 · see citing works
Passive Immunotherapies Targeting Amyloid-β in Alzheimer’s Disease: A Quantitative Systems Pharmacology Perspective
Marković, M., Milošević, J. R., Wang, W., & Cao, Y. (2023) · Molecular Pharmacology · doi:10.1124/molpharm.123.000726 · Cited by 19 · see citing works
Current Status and Challenges of Stem Cell Treatment for Alzheimer’s Disease
Pacheco‐Herrero, M., Soto-Rojas, L. O., Reyes-Sabater, H., Garcés‐Ramírez, L., de la Cruz‐López, F., Villanueva‐Fierro, I., & Luna‐Muñoz, J. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-200863 · Cited by 23 · see citing works
Non-Canonical Roles of Tau and Their Contribution to Synaptic Dysfunction
Siano, G., Falcicchia, C., Origlia, N., Cattaneo, A., & Primio, C. D. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221810145 · Cited by 19 · see citing works
RETRACTED ARTICLE: Efficacy and immunogenicity of MultiTEP-based DNA vaccines targeting human α-synuclein: prelude for IND enabling studies
Kim, C., Hovakimyan, A., Zagorski, K., Antonyan, T., Petrushina, I., Davtyan, H., Chailyan, G., Hasselmann, J., Iba, M., Adame, A., et al. (2022) · npj Vaccines · doi:10.1038/s41541-021-00424-2 · Cited by 19 · see citing works
Retracted
Targeting tau in Alzheimer’s and beyond: Insights into pathology and therapeutic strategies
Singh, S., Khan, S., Shahid, M., Sardar, M., Hassan, M. I., & Islam, A. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102639 · Cited by 19 · see citing works
Passive Immunotherapy Targeting Tau Oligomeric Strains Reverses Tauopathy Phenotypes in Aged Human-Tau Mice in a Mouse Model-Specific Manner
Bittar, A., Al-Lahham, R., Bhatt, N., Moore, K., Montalbano, M., Jerez, C., Fung, L., McAllen, S., Ellsworth, A., & Kayed, R. (2022) · Journal of Alzheimer's Disease · doi:10.3233/jad-220518 · Cited by 18 · see citing works
Key biomarkers in Alzheimer’s disease: Insights for diagnosis and treatment strategies
Jamal, R., Shaikh, M. A., Taleuzzaman, M., Haque, Z., Albratty, M., Alam, M. S., Makeen, H. A., Zoghebi, K. A., & Saleh, S. F. (2025) · Journal of Alzheimer s Disease · doi:10.1177/13872877251330500 · Cited by 19 · see citing works
“134 While MRI methods aid in tracking the course of the disease, neuroimaging biomarkers, such as tau-speci ﬁ c radiotracers and PET scans containing A β , provide important information about target engagement and therapy response.”
NMR Studies of Tau Protein in Tauopathies
Kitoka, K., Škrabana, R., Gašparik, N., Hritz, J., & Jaudzems, K. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.761227 · Cited by 18 · see citing works
“…become an appealing target for various therapeutic strategies including small-molecule inhibition of tau aggregation and phosphorylation, anti-sense oligonucleotide therapy, passive and active immunotherapy (Li and Götz, 2017; Novak et al., 2018b; Congdon and Sigurdsson, 2018; Jadhav et al., 2019).”
BackgroundInfluential
Improving Mouse Models for Dementia. Are All the Effects in Tau Mouse Models Due to Overexpression?Preprint
Joel, Z., Izquierdo, P., Salih, D. A. M., Richardson, J. C., Cummings, D. M., & Edwards, F. A. (2018) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2018.83.037531 · Cited by 18 · see citing works
“Furthermore, immunization with antibodies to Tau have been successful in ameliorating the effects of overexpression in several mouse models which may simply reflect loss of toxic overexpression rather than a clinically relevant effect (for review, see Novak et al. 2018).”
Background
In Vivo Validation of a Small Molecule Inhibitor of Tau Self-Association in htau Mice
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Anti-tau antibodies targeting a conformation-dependent epitope selectively bind seeds
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“40,44,45 Again, trials of interventions targeting tau have mostly used cognition as a primary outcome, with biomarkers included as secondary or exploratory outcomes.”
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A phase 1b/2a multicenter study of the safety and preliminary pharmacodynamic effects of selective muscarinic M 1 receptor agonist HTL0018318 in patients with mild‐to‐moderate Alzheimer's disease
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“To date, vaccinations against tau (Novak et al., 2018) and a-synuclein have advanced to phase II (Valera et al.”
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Additional file 3 of Anti-acetylated-tau immunotherapy is neuroprotective in tauopathy and brain injury
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Additional file 2 of Anti-acetylated-tau immunotherapy is neuroprotective in tauopathy and brain injury
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Additional file 1 of Anti-acetylated-tau immunotherapy is neuroprotective in tauopathy and brain injury
Parra Bravo, C., Krukowski, K., Barker, S., Wang, C., Li, Y., Fan, L., Vázquez‐Rosa, E., Shin, M.-K., Wong, M. Y., McCullough, L. D., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26094394
Additional file 4 of Anti-acetylated-tau immunotherapy is neuroprotective in tauopathy and brain injury
Parra Bravo, C., Krukowski, K., Barker, S., Wang, C., Li, Y., Fan, L., Vázquez‐Rosa, E., Shin, M.-K., Wong, M. Y., McCullough, L. D., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26738475
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Authors: Novak, P., Kontsekova, E., Zilka, N., & Novak, M.
Venue: Frontiers in Neuroscience
Publisher: Frontiers Media SA
Published: 2018-11-02
Volume: 12
Pages: 798-798
ISSN: 1662-453X (ISSN-L)
DOI: 10.3389/fnins.2018.00798
PMC: PMC6224648
OpenAlex: W2898989787
Cited by: 87
References: 141
Citations by year: 2026: 1 · 2025: 9 · 2024: 11 · 2023: 7 · 2022: 8 · 2021: 11 · 2020: 17 · 2019: 22 · 2018: 1
FWCI: 1.67
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
Locations: Frontiers in Neuroscience (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)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: tau pathology, tauopathy, Alzheimer's disease, epitope selection, anti-tau antibodies, immunosenescence, epitope evolution, behavioral variant frontotemporal dementia, Pick's disease, progressive supranuclear palsy, corticobasal degeneration, primary progressive aphasia

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Ten Years of Tau-Targeted Immunotherapy: The Path Walked and the Roads Ahead

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