Tau Reduction Diminishes Spatial Learning and Memory Deficits after Mild Repetitive Traumatic Brain Injury in Mice
Open accessAbstract
OBJECTIVE: Because reduction of the microtubule-associated protein Tau has beneficial effects in mouse models of Alzheimer's disease and epilepsy, we wanted to determine whether this strategy can also improve the outcome of mild traumatic brain injury (TBI). METHODS: We adapted a mild frontal impact model of TBI for wildtype C57Bl/6J mice and characterized the behavioral deficits it causes in these animals. The Barnes maze, Y maze, contextual and cued fear conditioning, elevated plus maze, open field, balance beam, and forced swim test were used to assess different behavioral functions. Magnetic resonance imaging (MRI, 7 Tesla) and histological analysis of brain sections were used to look for neuropathological alterations. We also compared the functional effects of this TBI model and of controlled cortical impact in mice with two, one or no Tau alleles. RESULTS: Repeated (2-hit), but not single (1-hit), mild frontal impact impaired spatial learning and memory in wildtype mice as determined by testing of mice in the Barnes maze one month after the injury. Locomotor activity, anxiety, depression and fear related behaviors did not differ between injured and sham-injured mice. MRI imaging did not reveal focal injury or mass lesions shortly after the injury. Complete ablation or partial reduction of tau prevented deficits in spatial learning and memory after repeated mild frontal impact. Complete tau ablation also showed a trend towards protection after a single controlled cortical impact. Complete or partial reduction of tau also reduced the level of axonopathy in the corpus callosum after repeated mild frontal impact. INTERPRETATION: Tau promotes or enables the development of learning and memory deficits and of axonopathy after mild TBI, and tau reduction counteracts these adverse effects.
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Tau ablation improves outcomes in models of TBI and high-salt diet-induced vascular dysfunction, with improvements in cognitive performance.
“Beyond neurodegenerative and neurodevelopmental disorders, tau ablation has also been shown to improve outcomes in models of neurological injury and vascular stress, such TBI and high-salt diet-induced vascular dysfunction, with associated improvements in cognitive performance [72, 86, 87].”
From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [86]
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- Authors
- Cheng, J. S., Craft, R., Yu, G.-Q., Ho, K., Wang, X., Mohan, G., Mangnitsky, S., Ponnusamy, R., & Mucke, L.
- Affiliations
- Gladstone Institutes (US)
- University of California, San Francisco (US)
- Corresponding author
- Mucke, Lennart
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-12-31
- Volume
- 9
- Issue
- 12
- Pages
- e115765
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4281043
- OpenAlex
- W2075949692
- Cited by
- 100
- References
- 44
- Citations by year
- 2026: 8 · 2025: 4 · 2024: 8 · 2023: 2 · 2022: 4 · 2021: 9 · 2020: 11 · 2019: 18 · 2018: 13 · 2017: 6 · 2016: 12 · 2015: 5
- FWCI
- 5.81
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Bristol-Myers Squibb
- Gladstone Institutes
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (NS065780, P30NS065780, R01NS041787, NS041787)
- Topics
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- tau protein, mild traumatic brain injury, spatial learning and memory deficits, axonopathy, corpus callosum, controlled cortical impact, fear conditioning, tau knockout mice
- MeSH terms
- Animals, Axons, Brain Injuries, Corpus Callosum, Disease Models, Animal, Female, Magnetic Resonance Imaging, Male, Memory, Memory Disorders, Mice, Inbred C57BL, tau Proteins, Mice, Knockout, Maze Learning, Mice, Spatial Learning
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