Immunotherapy Targeting Pathological Tau Conformers in a Tangle Mouse Model Reduces Brain Pathology with Associated Functional Improvements
Open accessAbstract
Immunotherapies for various neurodegenerative diseases have recently emerged as a promising approach for clearing pathological protein conformers in these disorders. This type of treatment has not been assessed in models that develop neuronal tau aggregates as observed in frontotemporal dementia and Alzheimer's disease. Here, we present that active immunization with a phosphorylated tau epitope, in P301L tangle model mice, reduces aggregated tau in the brain and slows progression of the tangle-related behavioral phenotype. Females had more tau pathology than males but were also more receptive to the immunotherapy. The tau antibodies generated in these animals recognized pathological tau on brain sections. Performance on behavioral assays that require extensive motor coordination correlated with tau pathology in corresponding brain areas, and antibody levels against the immunogen correlated inversely with tau pathology. Interestingly, age-dependent autoantibodies that recognized recombinant tau protein but not the immunogen were detected in the P301L mice. To confirm that anti-tau antibodies could enter the brain and bind to pathological tau, FITC-tagged antibodies purified from a P301L mouse, with a high antibody titer against the immunogen, were injected into the carotid artery of P301L mice. These antibodies were subsequently detected within the brain and colocalized with PHF1 and MC1 antibodies that recognize pathological tau. Currently, no treatment is available for clearing tau aggregates. Our present findings may lead to a novel therapy targeting one of the major hallmarks of Alzheimer's disease and frontotemporal dementia.
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Active and passive immunization against tau reduced pathological tau levels and attenuated behavioral phenotypes associated with tauopathy.
“Sigurdsson’s group was the first to report successful tau targeted therapy based on active and passive immunization against tau, which reduced pathological tau levels and attenuated the behavioral phenotypes associated with tauopathy.532”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [532]
The Abstract (page unavailable) reports that active immunization in P301L mice reduced aggregated brain tau and slowed progression of a tangle-related behavioral phenotype. It describes injected antibodies only as a test of whether they entered the brain and bound pathological tau; it does not report that passive immunization reduced pathology or improved behavior. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThe first reports of successful active and passive immunization against tau in a tauopathy mouse model, using a phospho-tau peptide comprising the pSer396/404 epitope or the PHF1 antibody against this epitope, came from our group.
“The first reports of successful active and passive immunization against tau in a tauopathy mouse model, using a phospho-tau peptide comprising the pSer396/404 epitope or the PHF1 antibody against this epitope185–188, came from our group.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [185]
Active tau immunization reduces tau pathology by targeting single or multiple phospho-epitopes, the amino terminus, full-length normal and mutant tau, or aggregated tau.
“Active tau immunization has been shown to reduce tau pathology by targeting single185, 187, 189–193 or multiple194 phospho-epitopes, the amino terminus195, full-length normal and mutant tau196, 197, or aggregated tau198.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [185]
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“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…”
BackgroundMethodResultInfluentialImmunotherapeutic Approaches for Alzheimer’s Disease
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“Several preclinical studies of immunotherapy targeting protein Tau have now been published [55–62].”
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Anti‐tau antibody reduces insoluble tau and decreases brain atrophy
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Distinct Therapeutic Mechanisms of Tau Antibodies
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- Authors
- Asuni, A. A., Boutajangout, A., Quartermain, D., & Sigurdsson, E. M.
- Affiliations
- New York University (US)
- Corresponding author
- Sigurdsson, Einar M.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2007-08-22
- Volume
- 27
- Issue
- 34
- Pages
- 9115-9129
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6672191
- OpenAlex
- W2121713269
- Cited by
- 506
- References
- 71
- Citations by year
- 2026: 6 · 2025: 15 · 2024: 21 · 2023: 20 · 2022: 16 · 2021: 17 · 2020: 33 · 2019: 31 · 2018: 37 · 2017: 32 · 2016: 27 · 2015: 43 · 2014: 49 · 2013: 38 · 2012: 30
- FWCI
- 13.59
- 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)
- ePrints Soton (University of Southampton) (submittedVersion)
- Funders
- Alzheimer's Association
- York University
- King's College London
- National Institutes of Health
- School of Medicine, New York University
- National Institute on Aging (R37AG005891, R01AG020197, AG 20197, AG5891)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tau immunotherapy, tau tangles, active immunization, anti-tau antibodies, Alzheimer's disease, frontotemporal dementia, sex differences, PHF1, motor coordination, neurodegeneration
- MeSH terms
- Age Factors, Analysis of Variance, Animals, Antibodies, Behavior, Animal, Brain, Dementia, Disease Models, Animal, Humans, Immunotherapy, Leucine, Mice, Transgenic, Motor Activity, Neuroblastoma, Proline, Psychomotor Performance, Sex Factors, tau Proteins, Recognition, Psychology, Cell Line, Tumor, Mice
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