Passive Immunotherapy Targeting Tau Oligomeric Strains Reverses Tauopathy Phenotypes in Aged Human-Tau Mice in a Mouse Model-Specific Manner
Abstract
Background: Tau oligomers are one of the most toxic species, displaying prion-like strains which have different conformations resulting in different tauopathies. Passive immunotherapy targeting different tau species is a promising therapeutic approach. Age is one of the greatest risk factors; however, most immunotherapy studies are done in young to middle-aged mice tauopathy models, which is not representative of the many clinical trials done with older humans with established tauopathies. Objective: We utilized two different clones of tau oligomer monoclonal antibodies (TOMAs) in aged Htau and JNPL3 mouse models to investigate the potential of passive immunotherapy. Methods: Aged mice received a single intravenous injection of 120 μg/animal of either TOMA1, TOMA3 clones or a non-specific IgG. Their cognitive functions were assessed one-week post-injection using Y-maze and novel object recognition tests. Brain tissues were analyzed using biochemical and immunological assays. Results: TOMA 1 and 3 rescues cognitive phenotypes in aged animals in a mouse model-specific manner, indicative by a reduction in tau oligomers levels. The TOMAs were shown to have strong reactivity with different tau oligomeric species in the different mouse models in vitro and ex vivo. Conclusion: This is the first study testing tau passive immunotherapy in aged animals and supports our previous reports on of the role of oligomeric tau in disease progression further validating the potential of TOMAs to rescue the late-stage disease pathology and phenotype. Moreover, this study suggests that multiple tau oligomeric strains exist in aged animals; therefore, it is of great importance to further characterize these strains.
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TauO, senescence, and inflammaging are crucial elements in Alzheimer's disease and may cooperatively trigger complex pathomechanisms involved in Alzheimer's disease progression and cognitive decline.
“These findings suggest that TauO, senescence, and inflammaging are crucial elements in AD and may cooperatively trigger the underlying complex pathomechanisms involved in AD progression and cognitive decline. 9 , 29 , 30 , 31 , 32 , 33”
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 [29]
Novel anti-tau antibodies specifically recognize disease-relevant tau strains and conformations.
“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 [29]
These anti-tau antibodies target unique conformational epitopes independent of specific linear amino acid sequences and exhibit preferences for different subsets of tau oligomers.
“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 [29]
Strain-specific immunotherapy for tau is still in preclinical stages.
“strain‐specific immunotherapy for tau is still in preclinical stages”
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 [29]
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- Authors
- Bittar, A., Al-Lahham, R., Bhatt, N., Moore, K., Montalbano, M., Jerez, C., Fung, L., McAllen, S., Ellsworth, A., & Kayed, R.
- Affiliations
- The University of Texas Medical Branch at Galveston (US)
- Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, USA
- MD Anderson Cancer Center, University of Texas, Houston, TX, USA
- Corresponding author
- Kayed, Rakez
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2022-11-22
- Volume
- 90
- Issue
- 3
- Pages
- 1103-1122
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W4298109598
- Cited by
- 18
- References
- 48
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 4 · 2023: 10
- FWCI
- 2.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- 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 oligomers, passive immunotherapy
- MeSH terms
- Animals, Antibodies, Monoclonal, Disease Models, Animal, Humans, Immunization, Passive, Mice, Transgenic, Phenotype, tau Proteins, Tauopathies, Mice
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