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Passive Immunization with Tau Oligomer Monoclonal Antibody Reverses Tauopathy Phenotypes without Affecting Hyperphosphorylated Neurofibrillary Tangles
Open accessAbstract
Recent findings suggest that tau oligomers, which form before neurofibrillary tangles (NFTs), are the true neurotoxic tau entities in neurodegenerative tauopathies, including Alzheimer's disease (AD). Studies in animal models of tauopathy suggest that tau oligomers play a key role in eliciting behavioral and cognitive impairments. Here, we used a novel tau oligomer-specific monoclonal antibody (TOMA) for passive immunization in mice expressing mutant human tau. A single dose of TOMA administered either intravenously or intracerebroventricularly was sufficient to reverse both locomotor and memory deficits in a mouse model of tauopathy for 60 d, coincident with rapid reduction of tau oligomers but not phosphorylated NFTs or monomeric tau. Our data demonstrate that antibody protection is mediated by extracellular and rapid peripheral clearance. These findings provide the first direct evidence in support of a critical role for tau oligomers in disease progression and validate tau oligomers as a target for the treatment of AD and other neurodegenerative tauopathies.
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“we observed elevated levels of TauO in the brain, cerebrospinal fluid (CSF), and sera from AD patients with clinical severity, 9 , 15 , 16 , 17 , 18 , 19 , 20”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [16]
In the citing paper
“significant advancements have been made in the development of novel anti‐tau antibodies that specifically recognize disease‐relevant tau strains and conformations.”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [16]
In the citing paper
“These antibodies target unique conformational epitopes, independent of specific linear amino acid sequences, and exhibit preferences for different subsets of tau oligomers.”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [16]
In the citing paper
“In addition, monoclonal antibodies against the amino-terminal or repeat domain (306–320) region209–215, oligomeric tau216,217, misfolded tau201,218,219, pSer202220,221, pThr231208 pSer409222, pSer413223 and pSer422224 have proved to be efficacious in tauopathy models.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [216]
In the citing paper
“Indeed, several reports are available of antibodies that are capable of reducing tau levels and preventing spreading without apparently entering neurons216,218,239.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [216]
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1 retracted
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“…exclusive and it has been demonstrated that different clearance mechanisms can be activated to different degrees depending on the antibody and its target (DeMattos et al., 2001; Levites et al., 2006; Sigurdsson, 2008; Golde et al., 2009; Masliah et al., 2011; Morgan, 2011; Ubhi and Masliah, 2011).”
BackgroundInfluentialRetractedSynapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model
Yoshiyama, Y., Higuchi, M., Zhang, B., Huang, S.-M., Iwata, N., Saido, T. C., Maeda, J., Suhara, T., Trojanowski, J. Q., & Lee, V. M.-Y. (2007) · Neuron · doi:10.1016/j.neuron.2007.01.010 · Cited by 2,208 · cited 1×
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BackgroundTau-mediated neurodegeneration in Alzheimer’s disease and related disorders
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“In addition, tau mutations can cause disorders such as familial frontotemporal dementia (for review, see Ballatore et al., 2007).”
BackgroundInfluentialTau Suppression in a Neurodegenerative Mouse Model Improves Memory Function
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Reducing Endogenous Tau Ameliorates Amyloid ß-Induced Deficits in an Alzheimer's Disease Mouse Model
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Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease
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BackgroundLewis, J., McGowan, E., Rockwood, J., Melrose, H., Nacharaju, P., Van Slegtenhorst, M., Gwinn-Hardy, K., Murphy, M. P., Baker, M., Yu, X., et al. (2000) · Nature Genetics · doi:10.1038/78078 · Cited by 1,371 · cited 3×
“The JNPL3 mouse model (Lewis et al., 2000) expresses a frontotemporal dementia-associated human mutant tau transgene (P301L) and has been used previously for tau immunotherapy (Asuni et al., 2007; Chai et al., 2011; Bi et al., 2011).”
MethodDeMattos, R. B., Bales, K. R., Cummins, D. J., Dodart, J.-C., Paul, S. M., & Holtzman, D. M. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.151261398 · Cited by 1,298
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Depletion of microglia and inhibition of exosome synthesis halt tau propagation
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The release and trans-synaptic transmission of Tau via exosomes
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Half a century of amyloids: past, present and future
Ke, P. C., Zhou, R., Serpell, L. C., Riek, R., Knowles, T. P. J., Lashuel, H. A., Gazit, E., Hamley, I. W., Davis, T. P., Fändrich, M., et al. (2020) · Chemical Society Reviews · doi:10.1039/c9cs00199a · Cited by 577
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Tau impairs neural circuits, dominating amyloid-β effects, in Alzheimer models in vivo
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Amyloid-β and tau complexity — towards improved biomarkers and targeted therapies
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Tau Aggregation and Its Interplay with Amyloid-β
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“Just days after the injections, immunized mice exhibited improved cognitive performance and motor activity, and a significant reduction in oligomeric tau levels in the brain and spinal cord [18].”
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Congdon, E. E., Ji, C., Tetlow, A. M., Jiang, Y., & Sigurdsson, E. M. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-023-00883-2 · Cited by 371
“Antibody treat-ment can increase serum tau levels, which might indicate removal from the brain via Fc receptors or, more likely, an increased half-life of antibody-bound tau 187–189 .”
BackgroundTau Oligomers: Cytotoxicity, Propagation, and Mitochondrial Damage
Shafiei, S. S., Guerrero-Muñoz, M. J., & Castillo-Carranza, D. L. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00083 · Cited by 314
“When tau oligomers, rather than tau monomers or fibrils, are injected into the brain of wild-type mice, cognitive, synaptic, and mitochondrial abnormalities follow (LasagnaReeves et al., 2011; Castillo-Carranza et al., 2014b).”
BackgroundSelf-citationA 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 299
Chen, X., & Mobley, W. C. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00659 · Cited by 302
“In vivo, using the hippocampal cognitive test just referenced, intravenous TOMA injection was shown to block the effect of intracerebroventricular (ICV) injection of AD brain-derived tau oligomers, an effect that was correlated with reduced levels of tau oligomers in the injected mouse brain (Castillo-Carranza et al.,…”
MethodSynaptic Tau Seeding Precedes Tau Pathology in Human Alzheimer’s Disease Brain
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“This therapy has been shown both in vitro and in vivo to be successful at preventing both tau pathology formation and propagation (Boimel et al., 2010; Bi et al., 2011; Yanamandra et al., 2013; Castillo-Carranza et al., 2014; Ittner et al., 2015; Nicholls et al., 2017; Nobuhara et al., 2017).”
BackgroundMechanisms of Cell-to-Cell Transmission of Pathological Tau: A Review
Gibbons, G. S., Lee, V. M. Y., & Trojanowski, J. Q. (2019) · JAMA Neurology · doi:10.1001/jamaneurol.2018.2505 · Cited by 257
Tau immunotherapy for Alzheimer's disease
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Ectosomes: A New Mechanism for Non-Exosomal Secretion of Tau Protein
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“Nevertheless, a recent study of Kayed’s group demonstrated that passive immunization with Tau oligomer monoclonal antibody reverses tauopathy phenotypes [64].”
BackgroundCollin, L., Bohrmann, B., Göpfert, U., Oroszlan‐Szovik, K., Ozmen, L., & Grüninger, F. (2014) · Brain · doi:10.1093/brain/awu213 · Cited by 208
“Several passive immunization studies in mice provide a strong rationale for developing tau immunotherapy for Alzheimer’s dis- ease (Boutajangout et al., 2011; Chai et al., 2011; d’Abramo et al., 2013; Castillo-Carranza et al., 2014).”
BackgroundInfluentialWobst, H. J., Sharma, A. M., Diamond, M. I., Wanker, E. E., & Bieschke, J. (2014) · FEBS Letters · doi:10.1016/j.febslet.2014.11.026 · Cited by 207
Intersection of pathological tau and microglia at the synapse
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“↓ P-tau, ↓insoluble tau, NC survival, NC micro- and astrogliosis Castillo-Carranza (2014) [53] TOMA (conformational) JPNL3 8M Single injection (30ug/mouse i.v. & 1ug/mouse i.c.v) ↓Tau oligomers, NC microgliosis and cytokines, improved cognition & motor deficits Castillo-Carranza (2014) [50] TOMA…”
BackgroundTau Assembly: The Dominant Role of PHF6 (VQIVYK) in Microtubule Binding Region Repeat R3
Ganguly, P., Do, T. D., Larini, L., LaPointe, N. E., Sercel, A. J., Shade, M. F., Feinstein, S. C., Bowers, M. T., & Shea, J. (2015) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.5b00175 · Cited by 194
From the prion-like propagation hypothesis to therapeutic strategies of anti-tau immunotherapy
Colin, M., Dujardin, S., Schraen-Maschke, S., Meno-Tetang, G., Duyckaerts, C., Courade, J.-P., & Buée, L. (2020) · Acta Neuropathologica · doi:10.1007/s00401-019-02087-9 · Cited by 187
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
“This type of mechanism was suggested by a recent study.(21) While there is as yet no direct evidence for this possibility, if future methods allow for detection of extracellular species of tau oligomers in vivo, this hypothesis may be testable.”
BackgroundNisbet, R. M., Van der Jeugd, A., Leinenga, G., Evans, H. T., Janowicz, P. W., & Götz, J. (2017) · Brain · doi:10.1093/brain/awx052 · Cited by 187
“Furthermore, immunization with anti-tau antibodies has proven efficacious in multiple preclinical models (Boutajangout et al., 2011; Yanamandra et al., 2013; Castillo-Carranza et al., 2014; Ittner et al., 2015).”
Prevention of tau seeding and propagation by immunotherapy with a central tau epitope antibody
Albert, M., Mairet‐Coello, G., Danis, C., Lieger, S., Caillierez, R., Carrier, S., Skrobala, E., Landrieu, I., Michel, A., Schmitt, M., et al. (2019) · Brain · doi:10.1093/brain/awz100 · Cited by 186
Targeting Amyloid Aggregation: An Overview of Strategies and Mechanisms
Giorgetti, S., Greco, C., Tortora, P., & Aprile, F. A. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19092677 · Cited by 179
“For example, camel single domain antibodies, generally referred as nanobodies, are extremely effective inhibitors of the aggregation of several amyloidogenic proteins, including lysozyme [63], α-synuclein (α-syn) [64], Aβ [65], tau [101], and β2-m [66].”
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 179
Nilson, A. N., English, K. C., Gerson, J. E., Whittle, T. B., Crain, C. N., Xue, J. J., Sengupta, U., Castillo‐Carranza, D. L., Zhang, W., Gupta, P. K., et al. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160912 · Cited by 178
Self-citationKanmert, D., Cantlon, A., Muratore, C., Jin, M., O’Malley, T. T., Lee, G. S., Young‐Pearse, T. L., Selkoe, D. J., & Walsh, D. M. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.0387-15.2015 · Cited by 169
“…released passively as a result of cell death or via active processes, the therapeutic use of antibodies that target aggregated tau or MTBR-containing aggregationcompetent forms of tau appear to offer great promise (Gu and Sigurdsson, 2011; Castillo-Carranza et al., 2014; Holmes and Diamond, 2014).”
BackgroundAmyloidogenesis of Tau protein
Niżyński, B., Dzwolak, W., & Nieznański, K. (2017) · Protein Science · doi:10.1002/pro.3275 · Cited by 166
Ghag, G., Bhatt, N. N., Cantu, D. V., Guerrero‐Munoz, M. J., Ellsworth, A., Sengupta, U., & Kayed, R. (2018) · Protein Science · doi:10.1002/pro.3499 · Cited by 161
Self-citationPassive 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 161
“A tau oligomer-selective monoclonal antibody (TOMA) was developed by Kayed and colleagues (Castillo-Carranza et al. (2014)), by immunizing BALB/c mice with recombinant (―synthetic‖) tau oligomers. TOMA is a murine IgG1 that selectively recognizes tau oligomers over either monomeric tau or tau NFTs. Its epitope has not…”
InfluentialCastillo-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
“Recently, we demonstrated that reduction of tau oligomers through passive immunization reversed cognitive and motor deficits associated with tau pathology in mice (Castillo-Carranza et al., 2014a,b).”
BackgroundMethodSelf-citationMotor and cognitive deficits in aged tau knockout mice in two background strains
Lei, P., Ayton, S., Moon, S., Zhang, Q., Volitakis, I., Finkelstein, D. I., & Bush, A. I. (2014) · Molecular Neurodegeneration · doi:10.1186/1750-1326-9-29 · Cited by 145
“reducing tau can ameliorate Aβ-induced toxicity [11,15,49,50] and rescue the toxicity in mouse mutant tau transgenic models [51-54].”
Stancu, I.-C., Vasconcelos, B., Ris, L., Wang, P., Villers, A., Peeraer, E., Buist, A., Terwel, D., Baatsen, P., Oyelami, T., et al. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1413-4 · Cited by 143
“These data are in line with clear demonstration of detrimental effects of Tau-oligomers on neuronal function and behavior, as demonstrated following acute injection of oligomeric Tau and immunization with anti-Tau oligomeric antibodies [10, 11, 39, 40].”
ResultTherapy 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 157
Derry, P. J., Hegde, M. L., Jackson, G. R., Kayed, R., Tour, J. M., Tsai, A.-L., & Kent, T. A. (2019) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2019.101716 · Cited by 146
“Passive immunization with TOMA against NFTs was not seen and TOMA was not observed to enter the cellular compartment suggesting a strictly extracellular role of the antibody (Castillo-Carranza et al., 2014).”
BackgroundSelf-citationThe role of tau in the pathological process and clinical expression of Huntington’s disease
Vuono, R., Winder‐Rhodes, S., de Silva, R., Cisbani, G., Drouin‐Ouellet, J., REGISTRY Investigators of the European Huntington’s Disease Network, Spillantini, M. G., Cicchetti, F., & Barker, R. A. (2015) · Brain · doi:10.1093/brain/awv107 · Cited by 139
New Insights Into Drug Discovery Targeting Tau Protein
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“These efforts have resulted in the generation of the TOC1 (Patterson et al., 2011), TOMA (Castillo-Carranza et al., 2014), and T22 (LasagnaReeves et al., 2012) antibodies that recognize intermediate tau aggregates.”
Niewiadomska, G., Niewiadomski, W., Steczkowska, M., & Gąsiorowska, A. (2021) · Life · doi:10.3390/life11010028 · Cited by 138
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Phagocytosis of full-length Tau oligomers by Actin-remodeling of activated microglia
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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
“Various tau antibodies directed against distinct epitopes have been tested, including N-terminal antibodies,(9,10) phospho-tauespecific antibodies, and conformation-dependent antibodies.(12,16) Some of these antibodies appear to ameliorate the cognitive impairments as well as the neuropathology of tau-transgenic mice;…”
BackgroundCerebral Microvascular Accumulation of Tau Oligomers in Alzheimer’s Disease and Related Tauopathies
Castillo-Carranza, D. L., Nilson, A. N., Van Skike, C. E., Jahrling, J. B., Patel, K., Garach, P., Gerson, J. E., Sengupta, U., Abisambra, J., Nelson, P., et al. (2017) · Aging and disease · doi:10.14336/ad.2017.0112 · Cited by 118
“Recently we demonstrated that specific removal of tau oligomers through passive immunotherapy using a tau oligomer-specific monoclonal antibody improves cognitive function without disrupting large NFTs in several tauopathy mouse models including the Tg2576, P301L, and Htau mice [38-41].”
BackgroundSelf-citationInsulin resistance in Alzheimer's disease
Dineley, K. T., Jahrling, J. B., & Denner, L. A. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.09.001 · Cited by 125
Self-citationThe Role of Tau Oligomers in the Onset of Alzheimer's Disease Neuropathology
Cárdenas-Aguayo, M. D. C., Gómez-Virgilio, L., DeRosa, S., & Meraz-Ríos, M. A. (2014) · ACS Chemical Neuroscience · doi:10.1021/cn500148z · Cited by 120
Wang, P., Joberty, G., Buist, A., Vanoosthuyse, A., Stancu, I., Vasconcelos, B., Pierrot, N., Faelth-Savitski, M., Kienlen‐Campard, P., Octave, J., et al. (2017) · Acta Neuropathologica · doi:10.1007/s00401-016-1663-9 · Cited by 120
“The detrimental role of Tau oligomers in neuronal function and behavior was further demonstrated using acute injection of oligomeric Tau and immunization with anti-Tau oligomeric antibodies [11, 12, 39, 40].”
BackgroundGaikwad, S., Senapati, S., Haque, M. A., & Kayed, R. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.13490 · Cited by 117
Self-citationRecent therapeutic strategies targeting beta amyloid and tauopathies in Alzheimer's disease
Madav, Y., Wairkar, S., & Prabhakar, B. R. (2019) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2019.01.004 · Cited by 122
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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
Ando, K., Maruko-Otake, A., Ohtake, Y., Hayashishita, M., Sekiya, M., & Iijima, K. M. (2016) · PLOS Genetics · doi:10.1371/journal.pgen.1005917 · Cited by 105
Dai, C.-L., Hu, W., Tung, Y. C., Liu, F., Gong, C.-X., & Iqbal, K. (2018) · Alzheimer's Research & Therapy · doi:10.1186/s13195-018-0341-7 · Cited by 99
“cits in a mouse model of tauopathy [39].”
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 113
Pathological Changes of Tau Related to Alzheimer’s Disease
Chu, D., & Liu, F. (2018) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.8b00457 · Cited by 106
Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy
Yanamandra, K., Patel, T. K., Jiang, H., Schindler, S., Ulrich, J. D., Boxer, A. L., Miller, B. L., Kerwin, D. R., Gallardo, G., Stewart, F., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aal2029 · Cited by 100
“First, whether all antitau antibodies will increase plasma tau as we report here is not yet known, although others have also observed increases in serum tau after administration of different anti-tau antibodies to tau Tg mice (16, 42).”
BackgroundErcan-Herbst, E., Ehrig, J., Schöndorf, D. C., Behrendt, A., Klaus, B., Gomez Ramos, B., Prat Oriol, N., Weber, C., & Ehrnhoefer, D. E. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0823-2 · Cited by 101
“To analyze different tau structures, conformationspecific antibodies have been developed, which are thought to react with the different folding states of the protein: Antibodies raised against oligomeric forms of tau such as T22, TOC1 and TOMA selectively label tau oligomers over monomers [24, 25, 32], whereas Alz50 a…”
BackgroundRao, 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 101
“Multiple antibodies, including Tau-5, T22, AT8, tau oligomer complex 1 (TOC1), and tau oligomer-specific monoclonal antibodies (TOMAs), have been used to detect tau species in the range of 100 –170 kDa, which have been termed tau multimers, oligomers, or highmolecular-weight tau-immunoreactive bands by different inves…”
BackgroundInfluentialTau forms oligomeric complexes on microtubules that are distinct from tau aggregates
Gyparaki, M. T., Arab, A., Sorokina, E. M., Santiago-Ruiz, A. N., Bohrer, C. H., Xiao, J., & Lakadamyali, M. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2021461118 · Cited by 97
“Moreover, injection of tau oligomers rather than monomers or fibrils into the brain of wild-type mice was sufficient to produce cognitive and synaptic abnormalities (15, 16).”
BackgroundCurrent Status of Clinical Trials on Tau Immunotherapies
Ji, C., & Sigurdsson, E. M. (2021) · Drugs · doi:10.1007/s40265-021-01546-6 · Cited by 96
Shulman, M. B., Kong, J., O'Gorman, J. T., Ratti, E., Rajagovindan, R., Viollet, L., Huang, E., Sharma, S., Racine, A. M., Czerkowicz, J., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00523-w · Cited by 100
Characterization of tau oligomeric seeds in progressive supranuclear palsy
Gerson, J. E., Sengupta, U., Lasagna‐Reeves, C. A., Guerrero‐Munoz, M. J., Troncoso, J. C., & Kayed, R. (2014) · Acta Neuropathologica Communications · doi:10.1186/2051-5960-2-73 · Cited by 102
“These results combined with recent studies showing the efficacy of passive immunotherapy targeting tau oligomers [44,45] support the possibility of utilizing this strategy for therapeutics in PSP, as well as in other neurodegenerative tauopathies.”
ResultSelf-citationDai, C., Chen, X., Kazim, S. F., Liu, F., Gong, C., Grundke, I., & Iqbal, K. (2014) · Journal of Neural Transmission · doi:10.1007/s00702-014-1315-y · Cited by 94
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
Dujardin, S., Colin, M., & Buée, L. (2014) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12200 · Cited by 101
Hussong, S. A., Banh, A. Q., Skike, C. E. V., Dorigatti, A. O., Hernandez, S. F., Hart, M. J., Ferrán, B., Makhlouf, H., Gaczynska, M. E., Osmulski, P. A., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-37840-y · Cited by 85
“Thus, whether the restoration of micro-vascular function by TOMA is driven by the removal of soluble tau aggregates from microvascular endothelial cells alone, or in combination with the removal of pathogenic tau from other brain cell types or potentially from cell types of the periphery cannot be ascertained from our…”
InfluentialSelf-citationTau‐targeting passive immunization modulates aspects of pathology in tau transgenic mice
Ittner, A., Bertz, J., Suh, L. S., Stevens, C. H., Götz, J., & Ittner, L. M. (2014) · Journal of Neurochemistry · doi:10.1111/jnc.12821 · Cited by 86
Is Huntington's disease a tauopathy?
Gratuze, M., Cisbani, G., Cicchetti, F., & Planel, E. (2016) · Brain · doi:10.1093/brain/aww021 · Cited by 81
Tau oligomers mediate α-synuclein toxicity and can be targeted by immunotherapy
Gerson, J. E., Farmer, K. M., Henson, N., Castillo‐Carranza, D. L., Murillo, M. C., Sengupta, U., Barrett, A. D. T., & Kayed, R. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0245-9 · Cited by 81
Self-citationRegulation of neuronal microtubule dynamics by tau: Implications for tauopathies
Venkatramani, A., & Panda, D. (2019) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2019.04.120 · Cited by 84
Tau oligomers in cerebrospinal fluid in Alzheimer's disease
Sengupta, U., Portelius, E., Hansson, O., Farmer, K., Castillo‐Carranza, D., Woltjer, R., Zetterberg, H., Galasko, D., Blennow, K., & Kayed, R. (2017) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.382 · Cited by 77
Self-citationSigurdsson, E. M. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-179937 · Cited by 76
“These include non-phosphorylated- [27,30,32,41,42,46–48,69,70], phosphorylated[20,24,25,27,29,35,39,43,49], conformational-/oligomeric [20,31,33,34,40,44,45], and a truncated epitope [66,71].”
The Role of Post-Translational Modifications on the Structure and Function of Tau Protein
Ye, H., Han, Y., Li, P., Su, Z., & Huang, Y. (2022) · Journal of Molecular Neuroscience · doi:10.1007/s12031-022-02002-0 · Cited by 76
“While the detailed conformations of tau oligomers remain unknown, they should be different from those of tau monomer and the hydrophobic segments in the MTBD may become more exposed (Castillo-Carranza et al. 2014; Lasagna-Reeves et al. 2010, 2012; Maeda et al. 2007; Mirbaha et al. 2018; Patterson et al. 2011).”
BackgroundPassive 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 74
“The clearance of extracellular tau by passive immunization may shift the equilibrium between the extracellular and intracellular tau pools, leading to the removal of intracellular tau.(37) Another plausible mechanism to the clearance of pathological tau could be lysosomes absorbing tau aggregates in the cytoplasm (via…”
BackgroundInfluentialLu, K. P., Kondo, A., Albayram, Ö., Herbert, M. K., Liu, H., & Zhou, X. Z. (2016) · JAMA Neurology · doi:10.1001/jamaneurol.2016.2027 · Cited by 74
Potential mechanisms and implications for the formation of tau oligomeric strains
Gerson, J. E., Mudher, A. K., & Kayed, R. (2016) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2016.1226251 · Cited by 78
Self-citationGerson, J. E., Castillo‐Carranza, D. L., & Kayed, R. (2014) · ACS Chemical Neuroscience · doi:10.1021/cn500143n · Cited by 75
Self-citationThe interrelationship of proteasome impairment and oligomeric intermediates in neurodegeneration
Deger, J. M., Gerson, J. E., & Kayed, R. (2015) · Aging Cell · doi:10.1111/acel.12359 · Cited by 69
“Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. in disease progression and validate tau oligomers as a potential drug target (Castillo-Carranza et al., 2013, 2014a,b).”
BackgroundSelf-citationToxic Tau Oligomers Modulated by Novel Curcumin Derivatives
Cascio, F. L., Puangmalai, N., Ellsworth, A., Bucchieri, F., Pace, A., Piccionello, A. P., & Kayed, R. (2019) · Scientific Reports · doi:10.1038/s41598-019-55419-w · Cited by 73
Self-citationPuangmalai, N., Sengupta, U., Bhatt, N., Gaikwad, S., Montalbano, M., Bhuyan, A., Garcia, S., McAllen, S., Sonawane, M., Jerez, C., et al. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101766 · Cited by 68
“Soluble tau oligomers have been identified as the more toxic species and most relevant to disease progression (8, 13).”
BackgroundSelf-citationTau 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
Amyloid-β oligomers as a template for secondary amyloidosis in Alzheimer's disease
Guerrero‐Munoz, M. J., Castillo‐Carranza, D. L., Krishnamurthy, S., Paulucci-Holthauzen, A. A., Sengupta, U., Lasagna‐Reeves, C. A., Ahmad, Y., Jackson, G. R., & Kayed, R. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.08.008 · Cited by 68
Self-citationViolet, M., Chauderlier, A., Delattre, L., Tardivel, M., Chouala, M. S., Sultan, A., Marciniak, E., Humez, S., Binder, L. I., Kayed, R., et al. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.09.003 · Cited by 80
Self-citationTargeting tau in Alzheimer's disease: from mechanisms to clinical therapy
Ye, J., Wan, H., Chen, S., & Liu, G. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.385847 · Cited by 74
“…(Asuni et al., 2007; Liu et al., 2016), p-Ser413 (Umeda et al., 2015), p-Ser422 (Collin et al., 2014; van Ameijde et al., 2018)), oligomeric tau (Castillo-Carranza et al., 2014; Bittar et al., 2022), fragmented tau (Dam et al., 2021), N-terminal tau (Dai et al., 2018), and total tau (Höglinger…”
Antibody-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
The Enigma of Tau Protein Aggregation: Mechanistic Insights and Future Challenges
Zheng, H., Sun, H., Cai, Q., & Tai, H. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25094969 · Cited by 69
“T22 (rabbit polyclonal) [179] and TOMA (mouse monoclonal) [180] were generated against oligomeric-A β -induced tau trimers.”
BackgroundAgadjanyan, M. G., Petrovsky, N., & Ghochikyan, A. (2015) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2015.06.1884 · Cited by 65
“Remarkably, a single intravenous injection of Mab cleared oligomeric tau, rescued the locomotor phenotype, and reversed the memory deficits associated with oligomeric tau pathology [154].”
BackgroundCongdon, E. E., Lin, Y., Rajamohamedsait, H. B., Shamir, D. B., Krishnaswamy, S., Rajamohamedsait, W. J., Rasool, S., González‐Calle, V., Levenga, J., Gu, J., et al. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0126-z · Cited by 64
“However, some antibodies do not appear to be taken up in appreciable amounts and are likely to primarily work extracellularly [15–17].”
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
Kayed, R., Dettmer, U., & Lesné, S. (2020) · Journal of Parkinson s Disease · doi:10.3233/jpd-201965 · Cited by 63
“Based on the properties of TOMA antibodies, which preferentially detect off-pathway o-Tau [205], and based on those for F8H7 and Syn33, which preferentially bind off-pathway o- Syn [89], these findings highlight complex molecular interactions between oSyn and o-Tau, which are not fully clear at this time.”
BackgroundSelf-citationTau Filament Self-Assembly and Structure: Tau as a Therapeutic Target
Oakley, S. S., Maina, M. B., Marshall, K. E., Al‐Hilaly, Y. K., Harrington, C., Wischik, C. M., & Serpell, L. C. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.590754 · Cited by 59
“In addition, following a decrease in oligomeric tau levels, improved cognitive function suggests the potential of anti-tau antibody infusions as a therapeutic approach (214).”
BackgroundPatel, H., Martínez, P., Perkins, A., Taylor, X., Jury, N., McKinzie, D. L., & Lasagna‐Reeves, C. A. (2021) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2021.09.006 · Cited by 58
Self-citationPhysiological clearance of tau in the periphery and its therapeutic potential for tauopathies
Wang, J., Jin, W., Bu, X., Zeng, F., Huang, Z., Li, W., Shen, L., Zhuang, Z., Fang, Y., Sun, B., et al. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1891-2 · Cited by 62
Congdon, E. E., Chukwu, J. E., Shamir, D. B., Deng, J., Ujla, D., Sait, H. B. R., Neubert, T. A., Kong, X., & Sigurdsson, E. M. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.03.033 · Cited by 56
Cox, K. K., Combs, B., Abdelmesih, B., Morfini, G. A., Brady, S. T., & Kanaan, N. M. (2016) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2016.07.015 · Cited by 62
“Indeed, multiple studies implicate oligomers as a primary toxic species of tau in several tauopathy model systems (Cardenas-Aguayo Mdel et al., 2014; Castillo-Carranza et al., 2014a; Fa et al., 2016; Gerson et al., 2016; Lewis and Dickson, 2016; Sahara et al., 2013; Tian et al., 2013; Usenovic et…”
Background
Metadata
- Authors
- Castillo-Carranza, D. L., Sengupta, U., Guerrero-Muñoz, M. J., Lasagna-Reeves, C. A., Gerson, J. E., Singh, G., Estes, D. M., Barrett, A. D. T., Dineley, K. T., Jackson, G. R., & Kayed, R.
- Affiliations
- The University of Texas Medical Branch at Galveston (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2014-03-19
- Volume
- 34
- Issue
- 12
- Pages
- 4260-4272
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6608097
- OpenAlex
- W1990986671
- Cited by
- 278
- References
- 76
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 15 · 2023: 21 · 2022: 13 · 2021: 20 · 2020: 30 · 2019: 25 · 2018: 34 · 2017: 27 · 2016: 21 · 2015: 28 · 2014: 23
- FWCI
- 21.94
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Drug Discovery Foundation
- 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 oligomers, passive immunization, monoclonal antibodies, TOMAS, tauopathy, Alzheimer's disease, neurofibrillary tangles, hyperphosphorylated tau, locomotor deficits, memory impairment, antibody clearance, neurodegenerative disease treatment
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Immunization, Passive, Phosphorylation, Neurofibrillary Tangles, tau Proteins, Disease Progression, Tauopathies, Mice
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