Modulation of Tau Isoforms Imbalance Precludes Tau Pathology and Cognitive Decline in a Mouse Model of Tauopathy
Open accessAbstract
The microtubule-associated protein tau regulates myriad neuronal functions, such as microtubule dynamics, axonal transport and neurite outgrowth. Tauopathies are neurodegenerative disorders characterized by the abnormal metabolism of tau, which accumulates as insoluble neuronal deposits. The adult human brain contains equal amounts of tau isoforms with three (3R) or four (4R) repeats of microtubule-binding domains, derived from the alternative splicing of exon 10 (E10) in the tau transcript. Several tauopathies are associated with imbalances of tau isoforms, due to splicing deficits. Here, we used a trans-splicing strategy to shift the inclusion of E10 in a mouse model of tauopathy that produces abnormal excess of 3R tau. Modulating the 3R/4R ratio in the prefrontal cortex led to a significant reduction of pathological tau accumulation concomitant with improvement of neuronal firing and reduction of cognitive impairments. Our results suggest promising potential for the use of RNA reprogramming in human neurodegenerative diseases.
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In Alzheimer's disease, tau undergoes hyperphosphorylation and other post-translational modifications, leading to aggregation into neurofibrillary tangles and disruption of neuronal function.
“In AD, tau undergoes hyperphosphorylation and other post-translational modifications, leading to its aggregation into neurofibrillary tangles (NFTs) and disruption of neuronal function [19, 23, 24].”
From Targeted Nanoparticles for Drug Delivery Across the Blood–Brain Barrier in Early and Late Stages of Alzheimer's Disease: A Review (2026) · cites this paper as [24]
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Age-Dependent Impairment of Cognitive and Synaptic Function in the htau Mouse Model of Tau Pathology
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Gourmaud, S., Shou, H., Irwin, D. J., Sansalone, K., Jacobs, L. M., Lucas, T. H., Marsh, E. D., Davis, K. A., Jensen, F. E., & Talos, D. M. (2020) · Brain · doi:10.1093/brain/awz381 · Cited by 155 · see citing works
Tau biology, tauopathy, traumatic brain injury, and diagnostic challenges
Castellani, R. J., & Perry, G. (2019) · Journal of Alzheimer’s Disease · doi:10.3233/jad-180721 · Cited by 110 · see citing works
Kochman, U., Sitka, H., Kuźniar, J., Czaja, M., Kozubek, P., Beszłej, J. A., & Leszek, J. (2026) · Molecular Neurobiology · doi:10.1007/s12035-025-05417-z · Cited by 60 · see citing works
- Authors
- Espíndola, S. L., Damianich, A., Alvarez, R. J., Sartor, M., Belforte, J. E., Ferrario, J. E., Gallo, J.-M., & Avale, M. E.
- Affiliations
- Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
- King's College London (GB)
- Corresponding author
- Avale, María Elena
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-04
- Volume
- 23
- Issue
- 3
- Pages
- 709-715
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2801680558
- Cited by
- 65
- References
- 3
- Citations by year
- 2026: 9 · 2025: 5 · 2024: 6 · 2023: 6 · 2022: 4 · 2021: 8 · 2020: 12 · 2019: 11 · 2018: 4
- FWCI
- 6.04
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Americanae (AECID Library) (submittedVersion, cc-by-nc-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Research Portal (King's College London) (submittedVersion, cc-by)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-sa)
- Funders
- International Brain Research Organization
- International Society for Neurochemistry (ISN-CAEN 2015)
- Ministerio de Ciencia, TecnologÃa e Innovación Productiva (PICT 2014-0459, PICT2013-1109)
- Consejo Nacional de Investigaciones CientÃficas y Técnicas
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- tau isoforms, tauopathy, trans-splicing, cognitive decline, prefrontal cortex, neuronal firing, neurodegenerative diseases, mouse model
- MeSH terms
- Animals, Disease Models, Animal, Exons, Male, RNA, Messenger, tau Proteins, Prefrontal Cortex, Alternative Splicing, Protein Isoforms, Tauopathies, Mice
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