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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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In the citing paper
“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
Masliah, E., Rockenstein, E. M., Mante, M., Crews, L. A., Spencer, B. J., Adame, A., Patrick, C., Trejo, M., Ubhi, K. K., Rohn, T. T., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0019338 · Cited by 422 · cited 5×
“…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×
“…metastable tau aggregates such as NFTs are not causally linked to tauopathy phenotypes in animal models (Wittmann et al., 2001; Santacruz et al., 2005; Berger et al., 2007; Yoshiyama et al., 2007; Polydoro et al., 2009; LasagnaReeves et al., 2011b; Spires-Jones et al., 2011; Cowan et al., 2012).”
BackgroundTau-mediated neurodegeneration in Alzheimer’s disease and related disorders
Ballatore, C., Lee, V. M.-Y., & Trojanowski, J. Q. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2194 · Cited by 2,174 · cited 3×
“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
SantaCruz, K., Lewis, J., Spires, T., Paulson, J., Kotilinek, L., Ingelsson, M., Guimaraes, A., DeTure, M., Ramsden, M., McGowan, E., et al. (2005) · Science · doi:10.1126/science.1113694 · Cited by 2,014
Bard, F., Cannon, C., Barbour, R., Burke, R.-L., Games, D., Grajeda, H., Guido, T., Hu, K., Huang, J., Johnson-Wood, K., et al. (2000) · Nature Medicine · doi:10.1038/78682 · Cited by 2,012
Reducing Endogenous Tau Ameliorates Amyloid ß-Induced Deficits in an Alzheimer's Disease Mouse Model
Roberson, E. D., Scearce-Levie, K., Palop, J. J., Yan, F., Cheng, I. H., Wu, T., Gerstein, H., Yu, G.-Q., & Mucke, L. (2007) · Science · doi:10.1126/science.1141736 · Cited by 1,892
Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease
Gómez‐Isla, T., Hollister, R., West, H., Mui, S., Growdon, J. H., Petersen, R. C., Parisi, J. E., & Hyman, B. T. (1997) · Annals of Neurology · doi:10.1002/ana.410410106 · Cited by 1,489 · cited 1×
“…human AD brain, NFT-containing neurons can survive for decades (Morsch et al., 1999) and neuronal loss precedes or is independent of NFT formation (Gómez-Isla et al., 1997; Terry, 2000; Maeda et al., 2006; van de Nes et al., 2008), suggesting that other tau species may contribute to earlier…”
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
Augustinack, J. C., Schneider, A., Mandelkow, E.-M., & Hyman, B. T. (2002) · Acta Neuropathologica · doi:10.1007/s004010100423 · Cited by 998
Tauopathy in Drosophila : Neurodegeneration Without Neurofibrillary Tangles
Wittmann, C. W., Wszolek, M. F., Shulman, J. M., Salvaterra, P. M., Lewis, J., Hutton, M., & Feany, M. B. (2001) · Science · doi:10.1126/science.1062382 · Cited by 939 · cited 1×
“…body of evidence suggests that large, metastable tau aggregates such as NFTs are not causally linked to tauopathy phenotypes in animal models (Wittmann et al., 2001; Santacruz et al., 2005; Berger et al., 2007; Yoshiyama et al., 2007; Polydoro et al., 2009; LasagnaReeves et al., 2011b;…”
BackgroundTau is essential to β-amyloid-induced neurotoxicity
Rapoport, M., Dawson, H. N., Binder, L. I., Vitek, M. P., & Ferreira, A. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.092136199 · Cited by 807
Oddo, S., Billings, L., Kesslak, J. P., Cribbs, D. H., & LaFerla, F. M. (2004) · Neuron · doi:10.1016/j.neuron.2004.07.003 · Cited by 780
Prion-like mechanisms in neurodegenerative diseases
Frost, B., & Diamond, M. I. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2786 · Cited by 776
Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice
Lasagna-Reeves, C. A., Castillo-Carranza, D. L., Sengupta, U., Clos, A. L., Jackson, G. R., & Kayed, R. (2011) · Molecular Neurodegeneration · doi:10.1186/1750-1326-6-39 · Cited by 633
Self-citationYanamandra, K., Kfoury, N., Jiang, H., Mahan, T. E., Ma, S., Maloney, S. E., Wozniak, D. F., Diamond, M. I., & Holtzman, D. M. (2013) · Neuron · doi:10.1016/j.neuron.2013.07.046 · Cited by 574
Trans-cellular Propagation of Tau Aggregation by Fibrillar Species
Kfoury, N., Holmes, B. B., Jiang, H., Holtzman, D. M., & Diamond, M. I. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.346072 · Cited by 552 · cited 1×
“As described recently in cell culture experiments, anti-tau antibodies can trap tau aggregates in the extracellular space and thus prevent the uptake and propagation of tau in adjacent cells (Kfoury et al., 2012).”
BackgroundEffects of α-Synuclein Immunization in a Mouse Model of Parkinson’s Disease
Masliah, E., Rockenstein, E., Adame, A., Alford, M., Crews, L., Hashimoto, M., Seubert, P., Lee, M., Goldstein, J., Chilcote, T., et al. (2005) · Neuron · doi:10.1016/j.neuron.2005.05.010 · Cited by 542
Wu, J. W., Herman, M., Liu, L., Simoes, S., Acker, C. M., Figueroa, H., Steinberg, J. I., Margittai, M., Kayed, R., Zurzolo, C., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.394528 · Cited by 537 · cited 3×
“, tau oligomeric intermediates) in tauopathies is poorly understood; however, novel polyclonal and monoclonal antibodies that define specific tau species have enabled the study of tau oligomers in vivo (Patterson et al., 2011; Lasagna-Reeves et al., 2012a; Blair et al., 2013; Hawkins et al., 2013; Wu et al., 2013).”
BackgroundSelf-citationIdentification of oligomers at early stages of tau aggregation in Alzheimer's disease
Lasagna‐Reeves, C. A., Castillo‐Carranza, D. L., Sengupta, U., Sarmiento, J., Troncoso, J., Jackson, G. R., & Kayed, R. (2012) · The FASEB Journal · doi:10.1096/fj.11-199851 · Cited by 527 · cited 29×
“We also showed that AD-brain-derived tau oligomers isolated using T22 disrupt memory and propagate the abnormal conformation of endogenous tau in wild-type mice, implicating tau oligomers in the spread of pathology but not NFTs (Lasagna-Reeves et al., 2012b).”
BackgroundMethodResultInfluentialSelf-citationAsuni, A. A., Boutajangout, A., Quartermain, D., & Sigurdsson, E. M. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.2361-07.2007 · Cited by 506 · cited 8×
“A possible explanation for this is that previous studies (Asuni et al., 2007; Boimel et al., 2010; Boutajangout et al., 2011; Chai et al., 2011; Gu and Sigurdsson, 2011; Bi et al., 2011) specifically targeted tau pathology using phosphorylated antigens or antibodies directed against p-epitopes…”
BackgroundMethodResultInfluentialAccumulation of Pathological Tau Species and Memory Loss in a Conditional Model of Tauopathy
Berger, Z., Roder, H. M., Hanna, A., Carlson, A. M., Rangachari, V., Yue, M., Wszołek, Z. K., Ashe, K. H., Knight, J. A., Dickson, D. W., et al. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.0587-07.2007 · Cited by 503 · cited 1×
“…metastable tau aggregates such as NFTs are not causally linked to tauopathy phenotypes in animal models (Wittmann et al., 2001; Santacruz et al., 2005; Berger et al., 2007; Yoshiyama et al., 2007; Polydoro et al., 2009; LasagnaReeves et al., 2011b; Spires-Jones et al., 2011; Cowan et al., 2012).”
BackgroundAlzheimer brain-derived tau oligomers propagate pathology from endogenous tau
Lasagna-Reeves, C. A., Castillo-Carranza, D. L., Sengupta, U., Guerrero-Munoz, M. J., Kiritoshi, T., Neugebauer, V., Jackson, G. R., & Kayed, R. (2012) · Scientific Reports · doi:10.1038/srep00700 · Cited by 502
Self-citationTai, H.-C., Serrano-Pozo, A., Hashimoto, T., Frosch, M. P., Spires-Jones, T. L., & Hyman, B. T. (2012) · The American Journal of Pathology · doi:10.1016/j.ajpath.2012.06.033 · Cited by 443 · cited 2×
“, 2012), impairing the ubiquitin-proteasome system (Tai et al., 2012) and contributing to synaptic dysfunction and loss.”
BackgroundNeurons May Live for Decades with Neurofibrillary Tangles
Morsch, R., Simon, W., & Coleman, P. D. (1999) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/00005072-199902000-00008 · Cited by 370 · cited 2×
“Furthermore, in human AD brain, NFT-containing neurons can survive for decades (Morsch et al., 1999) and neuronal loss precedes or is independent of NFT formation (Gómez-Isla et al., 1997; Terry, 2000; Maeda et al., 2006; van de Nes et al., 2008), suggesting that other tau species may contribute…”
BackgroundCharacterization of Prefibrillar Tau Oligomers in Vitro and in Alzheimer Disease
Patterson, K. R., Remmers, C. L., Fu, Y., Brooker, S. M., Kanaan, N. M., Vana, L., Ward, S., Reyes, J. F., Philibert, K., Glucksman, M., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.237974 · Cited by 369 · cited 4×
“The therapeutic effects of the TOMA antibody in P301L results in a reduction of pathogenic tau oligomers coinciding with the rescue of tauopathy-related motor and cognitive phenotypes in mice, reinforcing the concept that oligomers are the pathological form of tau in animal models of neurodegenerative tauopathy (Lasag…”
BackgroundInfluentialPassive Immunization with Anti-Tau Antibodies in Two Transgenic Models
Chai, X., Wu, S., Murray, T. K., Kinley, R. D., Cella, C. V., Sims, H., Buckner, N., Hanmer, J. M., Davies, P., O’Neill, M. J., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.229633 · Cited by 363
Preparation and Characterization of Neurotoxic Tau Oligomers
Lasagna-Reeves, C. A., Castillo-Carranza, D. L., Guerrero-Muñoz, M. J., Jackson, G. R., & Kayed, R. (2010) · Biochemistry · doi:10.1021/bi1016233 · Cited by 359
Self-citationHolcomb, L. A., Gordon, M. N., Jantzen, P., Hsiao, K., Duff, K., & Morgan, D. (1999) · Behavior Genetics · doi:10.1023/a:1021691918517 · Cited by 353 · cited 1×
“To determine the effect of immunotherapy on behavioral deficits, the spatial memory and motor function of P301L and wildtype mice were evaluated by rotarod and Y-maze tests (Holcomb et al., 1999; Morgan et al., 2008).”
MethodAntibody-Aided Clearance of Extracellular α-Synuclein Prevents Cell-to-Cell Aggregate Transmission
Bae, E.-J., Lee, H.-J., Rockenstein, E., Ho, D.-H., Park, E.-B., Yang, N.-Y., Desplats, P., Masliah, E., & Lee, S.-J. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.1292-12.2012 · Cited by 339 · cited 1×
“Moreover, another study demonstrated that the clearance of extracellular -synuclein by passive immunization prevents cell-to-cell aggregate transmission and ameliorates neurodegeneration and behavioral deficits (Bae et al., 2012; Yanamandra et al., 2013).”
BackgroundAge-Dependent Impairment of Cognitive and Synaptic Function in the htau Mouse Model of Tau Pathology
Polydoro, M., Acker, C. M., Duff, K., Castillo, P. E., & Davies, P. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.1065-09.2009 · Cited by 329 · cited 1×
“…metastable tau aggregates such as NFTs are not causally linked to tauopathy phenotypes in animal models (Wittmann et al., 2001; Santacruz et al., 2005; Berger et al., 2007; Yoshiyama et al., 2007; Polydoro et al., 2009; LasagnaReeves et al., 2011b; Spires-Jones et al., 2011; Cowan et al., 2012).”
BackgroundAccelerated neurodegeneration through chaperone-mediated oligomerization of tau
Blair, L. J., Nordhues, B. A., Hill, S. E., Scaglione, K. M., O’Leary, J. C., Fontaine, S. N., Breydo, L., Zhang, B., Li, P., Wang, L., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci69003 · Cited by 322 · cited 2×
“, tau oligomeric intermediates) in tauopathies is poorly understood; however, novel polyclonal and monoclonal antibodies that define specific tau species have enabled the study of tau oligomers in vivo (Patterson et al., 2011; Lasagna-Reeves et al., 2012a; Blair et al., 2013; Hawkins et al., 2013; Wu et al., 2013).”
BackgroundSelf-citationBoutajangout, A., Ingadottir, J., Davies, P., & Sigurdsson, E. M. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07337.x · Cited by 306 · cited 3×
“The dose used in this study was 5- to 10-fold lower than those previously used to nonselectively target tau aggregates by passive immunotherapy (Boutajangout et al., 2011; Chai et al., 2011), which may also contribute to increased safety while maintaining efficacy because oligomers represent a small percentage of tota…”
BackgroundMethodWilcock, D. M., Rojiani, A. M., Rosenthal, A., Levkowitz, G., Subbarao, S., Alamed, J., Wilson, D. H., Wilson, N., Freeman, M. J., Gordon, M. N., et al. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.1090-04.2004 · Cited by 302
Increased levels of granular tau oligomers: An early sign of brain aging and Alzheimer's disease
Maeda, S., Sahara, N., Saito, Y., Murayama, S., Ikai, A., & Takashima, A. (2006) · Neuroscience Research · doi:10.1016/j.neures.2005.11.009 · Cited by 301 · cited 1×
“…NFT-containing neurons can survive for decades (Morsch et al., 1999) and neuronal loss precedes or is independent of NFT formation (Gómez-Isla et al., 1997; Terry, 2000; Maeda et al., 2006; van de Nes et al., 2008), suggesting that other tau species may contribute to earlier stages of disease.”
BackgroundBlood–brain barrier impairment in Alzheimer disease
Bowman, G. L., Kaye, J. A., Moore, M., Waichunas, D., Carlson, N. E., & Quinn, J. F. (2007) · Neurology · doi:10.1212/01.wnl.0000262031.18018.1a · Cited by 294
Template-assisted filament growth by parallel stacking of tau
Margittai, M., & Langen, R. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0401911101 · Cited by 276
Wilcock, D. M., DiCarlo, G., Henderson, D., Jackson, J., Clarke, K., Ugen, K. E., Gordon, M. N., & Morgan, D. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-09-03745.2003 · Cited by 232
Immunotherapy for Alzheimer’s disease: Key Symposium: Immunotherapy for Alzheimer’s disease
Morgan, D. (2011) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2010.02315.x · Cited by 225
Ma, Q., Zuo, X., Yang, F., Ubeda, O. J., Gant, D. J., Alaverdyan, M., Teng, E., Hu, S., Chen, P., Maiti, P., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.393751 · Cited by 220 · cited 1×
“Furthermore, it has been reported that reduction of soluble tau oligomers after treatment with curcumin rescues synaptic and behavioral deficits in aged tau transgenic mice (Ma et al., 2013).”
BackgroundInflammation Induced by Infection Potentiates Tau Pathological Features in Transgenic Mice
Sy, M., Kitazawa, M., Medeiros, R., Whitman, L., Cheng, D., Lane, T. E., & LaFerla, F. M. (2011) · The American Journal of Pathology · doi:10.1016/j.ajpath.2011.02.012 · Cited by 210
Zommer, N., Sergeant, N., Schraen-Maschke, S., Blum, D., & Buee, L. (2012) · Current Alzheimer Research · doi:10.2174/156720512800492503 · Cited by 193 · cited 1×
“A similar sample size in another tau immunotherapy study was found to be suitable to detect significant differences for the Y-maze task as well (Troquier et al., 2012).”
Tauopathy-like Abnormalities and Neurologic Deficits in Mice Immunized With Neuronal Tau Protein
Rosenmann, H., Grigoriadis, N., Karussis, D., Boimel, M., Touloumi, O., Ovadia, H., & Abramsky, O. (2006) · Archives of Neurology · doi:10.1001/archneur.63.10.1459 · Cited by 178 · cited 1×
“Because tau is an endogenous protein with normal cellular functions, such treatments carry the risk of inducing autoimmunity and/or other related complications (Rosenmann et al., 2006).”
BackgroundEfficacy and safety of immunization with phosphorylated tau against neurofibrillary tangles in mice
Boimel, M., Grigoriadis, N., Lourbopoulos, A., Haber, E., Abramsky, O., & Rosenmann, H. (2010) · Experimental Neurology · doi:10.1016/j.expneurol.2010.05.010 · Cited by 174 · cited 2×
“Active vaccination using phosphorylated tau fragments (Asuni et al., 2007; Boimel et al., 2010; Bi et al., 2011), and passive vaccination using antibodies directed against NFT-associated tau phosphoepitopes (Boutajangout et al., 2011; Chai et al., 2011; Gu and Sigurdsson, 2011) have been reported…”
BackgroundRapid Accumulation of Endogenous Tau Oligomers in a Rat Model of Traumatic Brain Injury
Hawkins, B. E., Krishnamurthy, S., Castillo‐Carranza, D. L., Sengupta, U., Prough, D. S., Jackson, G. R., DeWitt, D. S., & Kayed, R. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.472746 · Cited by 153 · cited 2×
“, tau oligomeric intermediates) in tauopathies is poorly understood; however, novel polyclonal and monoclonal antibodies that define specific tau species have enabled the study of tau oligomers in vivo (Patterson et al., 2011; Lasagna-Reeves et al., 2012a; Blair et al., 2013; Hawkins et al., 2013; Wu et al., 2013).”
BackgroundSelf-citationBi, M., Ittner, A., Ke, Y. D., Götz, J., & Ittner, L. M. (2011) · PLoS ONE · doi:10.1371/journal.pone.0026860 · Cited by 153 · cited 4×
“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).”
BackgroundMethodInfluentialTau-Based Treatment Strategies in Neurodegenerative Diseases
Schneider, A., & Mandelkow�, E. (2008) · Neurotherapeutics · doi:10.1016/j.nurt.2008.05.006 · Cited by 145 · cited 1×
“…(Ballatore et al., 2007; Haroutunian et al., 2007) and amyloid- (A )- mediated neurotoxicity (Rapoport et al., 2002; Roberson et al., 2007), tau-based therapeutic approaches have lagged behind those targeting A (Schneider and Mandelkow, 2008; LasagnaReeves et al., 2011b; Ubhi and Masliah, 2011).”
BackgroundTau Passive Immunotherapy in Mutant P301L Mice: Antibody Affinity versus Specificity
d’Abramo, C., Acker, C. M., Jimenez, H. T., & Davies, P. (2013) · PLoS ONE · doi:10.1371/journal.pone.0062402 · Cited by 144
Formation and Propagation of Tau Oligomeric Seeds
Gerson, J. E., & Kayed, R. (2013) · Frontiers in Neurology · doi:10.3389/fneur.2013.00093 · Cited by 140
Self-citationAmyloid-β Annular Protofibrils Evade Fibrillar Fate in Alzheimer Disease Brain
Lasagna‐Reeves, C. A., Glabe, C. G., & Kayed, R. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.236257 · Cited by 139
Self-citationLemere, C. A. (2003) · Neurobiology of Disease · doi:10.1016/s0969-9961(03)00044-5 · Cited by 139 · cited 1×
“The mechanism of tau oligomer clearance appears to occur via a peripheral pathway similar to several previously described for the clearance of other amyloid proteins (DeMattos et al., 2001; Lemere et al., 2003; Oddo et al., 2004; Masliah et al., 2005; Winkler et al., 2010).”
Thakker, D. R., Weatherspoon, M. R., Harrison, J., Keene, T. E., Lane, D. S., Kaemmerer, W. F., Stewart, G. R., & Shafer, L. L. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0813404106 · Cited by 124 · cited 2×
“…phenotypes and specifically clears tau oligomers in P301L mice Injection of anti-amyloid antibodies in AD animal models via intracerebroventricular injection has been performed in a few well executed studies (Chauhan and Siegel, 2003; Oddo et al., 2004; Chauhan, 2007; Thakker et al., 2009).”
MethodYamada, K., Yabuki, C., Seubert, P., Schenk, D., Hori, Y., Ohtsuki, S., Terasaki, T., Hashimoto, T., & Iwatsubo, T. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.2021-09.2009 · Cited by 117
Immunotherapy Targeting Pathological Tau Protein in Alzheimer's Disease and Related Tauopathies
Sigurdsson, E. M. (2008) · Journal of Alzheimer's Disease · doi:10.3233/jad-2008-15202 · Cited by 116 · cited 2×
“…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).”
BackgroundInsights into the mechanisms of action of anti‐Aβ antibodies in Alzheimer's disease mouse models
Levites, Y., Smithson, L. A., Price, R. W., Dakin, R. S., Yuan, B., Sierks, M. R., Kim, J., McGowan, E., Kim Reed, D., Rosenberry, T. L., et al. (2006) · The FASEB Journal · doi:10.1096/fj.06-6463fje · Cited by 113
Are Tangles as Toxic as They Look?
Spires-Jones, T. L., Kopeikina, K. J., Koffie, R. M., de Calignon, A., & Hyman, B. T. (2011) · Journal of Molecular Neuroscience · doi:10.1007/s12031-011-9566-7 · Cited by 104 · cited 1×
“…metastable tau aggregates such as NFTs are not causally linked to tauopathy phenotypes in animal models (Wittmann et al., 2001; Santacruz et al., 2005; Berger et al., 2007; Yoshiyama et al., 2007; Polydoro et al., 2009; LasagnaReeves et al., 2011b; Spires-Jones et al., 2011; Cowan et al., 2012).”
BackgroundFox, L. M., William, C. M., Adamowicz, D. H., Pitstick, R., Carlson, G. A., Spires-Jones, T. L., & Hyman, B. T. (2011) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e318220a658 · Cited by 88 · cited 1×
“In addition, environmental enrichment reduced soluble tau and restored Arc messenger RNA levels in rTg4510-transgenic mice overexpressing P301L mutant human tau protein despite the continued presence of NFT pathology (Fox et al., 2011).”
BackgroundTau protein abnormalities associated with the progression of alzheimer disease type dementia
Haroutunian, V., Davies, P., Vianna, C., Buxbaum, J. D., & Purohit, D. P. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.11.001 · Cited by 86
Tau Oligomers as Potential Targets for Immunotherapy for Alzheimers Disease and Tauopathies
A. Lasagna-Reeves, C., L. Castillo-Carranza, D., R. Jackson, G., & Kayed, R. (2011) · Current Alzheimer Research · doi:10.2174/156720511796717177 · Cited by 80 · cited 2×
“The supernatants were aliquoted, snap-frozen, and stored at 80°C until use (Lasagna-Reeves et al., 2011a).”
BackgroundMethodSelf-citationKrishnamurthy, P., Deng, Y., & Sigurdsson, E. M. (2011) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2011.00059 · Cited by 73 · cited 2×
“The supernatants were aliquoted, snap-frozen, and stored at 80°C until use (Lasagna-Reeves et al., 2011a).”
BackgroundMethodExtensive p‐Tau Pathology and SDS‐Stable p‐Tau Oligomers in Alzheimer's Cortical Synapses
Henkins, K. M., Sokolow, S., Miller, C. A., Vinters, H. V., Poon, W. W., Cornwell, L. B., Saing, T., & Gylys, K. H. (2012) · Brain Pathology · doi:10.1111/j.1750-3639.2012.00598.x · Cited by 69 · cited 2×
“Furthermore, widespread tau oligomers accumulate at the synapses (Henkins et al., 2012), impairing the ubiquitin-proteasome system (Tai et al.”
BackgroundTau Oligomers as Potential Targets for Alzheimer’s Diagnosis and Novel Drugs
Guzmán‐Martínez, L., Farias, G. A., & Maccioni, R. B. (2013) · Frontiers in Neurology · doi:10.3389/fneur.2013.00167 · Cited by 62 · cited 1×
“In summary, our studies support the notion that tau oligomer immunization strategies may be beneficial for AD and other tauopathies (Guzmán-Martinez et al., 2013).”
BackgroundWhat is the pathological significance of tau oligomers?
Cowan, C. M., Quraishe, S., & Mudher, A. K. (2012) · Biochemical Society Transactions · doi:10.1042/bst20120135 · Cited by 62 · cited 3×
“The therapeutic effects of the TOMA antibody in P301L results in a reduction of pathogenic tau oligomers coinciding with the rescue of tauopathy-related motor and cognitive phenotypes in mice, reinforcing the concept that oligomers are the pathological form of tau in animal models of neurodegenerative tauopathy (Lasag…”
BackgroundDo neuronal inclusions kill the cell?
Terry, R. (2000) · Springer eBooks · doi:10.1007/978-3-7091-6781-6_12 · Cited by 48 · cited 1×
“…NFT-containing neurons can survive for decades (Morsch et al., 1999) and neuronal loss precedes or is independent of NFT formation (Gómez-Isla et al., 1997; Terry, 2000; Maeda et al., 2006; van de Nes et al., 2008), suggesting that other tau species may contribute to earlier stages of disease.”
BackgroundApparent Behavioral Benefits of Tau Overexpression in P301L Tau Transgenic Mice
Morgan, D., Munireddy, S., Alamed, J., DeLeon, J., Diamond, D. M., Bickford, P. C., Hutton, M. L., Lewis, J. M., McGowan, E. M., & Gordon, M. N. (2008) · Journal of Alzheimer s Disease · doi:10.3233/jad-2008-15407 · Cited by 46 · cited 1×
“To determine the effect of immunotherapy on behavioral deficits, the spatial memory and motor function of P301L and wildtype mice were evaluated by rotarod and Y-maze tests (Holcomb et al., 1999; Morgan et al., 2008).”
MethodQuantitative and Mechanistic Studies of Aβ Immunotherapy
Golde, T., Das, P., & Levites, Y. (2009) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152709787601830 · Cited by 46
Intracerebroventricular passive immunization with anti‐Aβ antibody in Tg2576
Chauhan, N. B., & Siegel, G. J. (2003) · Journal of Neuroscience Research · doi:10.1002/jnr.10721 · Cited by 45 · cited 2×
“…phenotypes and specifically clears tau oligomers in P301L mice Injection of anti-amyloid antibodies in AD animal models via intracerebroventricular injection has been performed in a few well executed studies (Chauhan and Siegel, 2003; Oddo et al., 2004; Chauhan, 2007; Thakker et al., 2009).”
Methodvan de Nes, J. A. P., Nafe, R., & Schlote, W. (2008) · Brain Research · doi:10.1016/j.brainres.2008.03.043 · Cited by 42
Gu, J., & Sigurdsson, E. M. (2011) · Journal of Molecular Neuroscience · doi:10.1007/s12031-011-9576-5 · Cited by 36 · cited 2×
“…using phosphorylated tau fragments (Asuni et al., 2007; Boimel et al., 2010; Bi et al., 2011), and passive vaccination using antibodies directed against NFT-associated tau phosphoepitopes (Boutajangout et al., 2011; Chai et al., 2011; Gu and Sigurdsson, 2011) have been reported in animal models.”
BackgroundTau aggregates as immunotherapeutic targets.
Castillo-Carranza, D. L., Lasagna-Reeves, C., & Kayed, R. (2013) · Frontiers in Bioscience · doi:10.2741/s381 · Cited by 33
Self-citationIntracerebroventricular passive immunization with anti‐oligoAβ antibody in TgCRND8
Chauhan, N. B. (2007) · Journal of Neuroscience Research · doi:10.1002/jnr.21110 · Cited by 24 · cited 2×
“…phenotypes and specifically clears tau oligomers in P301L mice Injection of anti-amyloid antibodies in AD animal models via intracerebroventricular injection has been performed in a few well executed studies (Chauhan and Siegel, 2003; Oddo et al., 2004; Chauhan, 2007; Thakker et al., 2009).”
MethodRecent advances in the development of immunotherapies for tauopathies
Ubhi, K. K., & Masliah, E. (2010) · Experimental Neurology · doi:10.1016/j.expneurol.2010.10.007 · Cited by 16 · cited 7×
“…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).”
BackgroundInfluentialImmunotherapy for the treatment of Alzheimer's disease: amyloid-β or tau, which is the right target?
Kayed, R., Castillo‐Carranza, D. L., & Guerrero‐Munoz, M. J. (2013) · ImmunoTargets and Therapy · doi:10.2147/itt.s40131 · Cited by 16
Self-citationWinkler, D. T., Abramowski, D., Danner, S., Zurini, M. G. M., Paganetti, P., Tolnay, M., & Staufenbiel, M. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.01.030 · Cited by 14
Gallyas, F. (2008) · Biotechnic & Histochemistry · doi:10.1080/10520290802538543 · Cited by 13
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Tau in physiology and pathology
Wang, Y., & Mandelkow, E. (2016) · Nature Reviews Neuroscience · doi:10.1038/nrn.2015.1 · Cited by 2,251
Clearance systems in the brain—implications for Alzheimer disease
Tarasoff-Conway, J. M., Carare, R. O., Osorio, R. S., Glodzik, L., Butler, T., Fieremans, E., Axel, L., Rusinek, H., Nicholson, C., Zlokovic, B. V., et al. (2015) · Nature Reviews Neurology · doi:10.1038/nrneurol.2015.119 · Cited by 1,678
Depletion of microglia and inhibition of exosome synthesis halt tau propagation
Asai, H., Ikezu, S., Tsunoda, S., Medalla, M., Luebke, J., Haydar, T., Wolozin, B., Butovsky, O., Kügler, S., & Ikezu, T. (2015) · Nature Neuroscience · doi:10.1038/nn.4132 · Cited by 1,591
Tau-targeting therapies for Alzheimer disease
Congdon, E. E., & Sigurdsson, E. M. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0013-z · Cited by 1,113
Tau and neurodegenerative disease: the story so far
Iqbal, K., Liu, F., & Gong, C.-X. (2016) · Nature Reviews Neurology · doi:10.1038/nrneurol.2015.225 · Cited by 806
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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