The effects of mild closed head injuries on tauopathy and cognitive deficits in rodents: Primary results in wild type and rTg4510 mice, and a systematic review

Bachstetter, Adam D.; Morganti, Josh M.; Bodnar, Colleen N.; Webster, Scott J.; Higgins, Emma K.; Roberts, Kelly N.; Snider, Henry; Meier, Shelby E.; Nation, Grant K.; Goulding, Danielle S.; Hamm, Matthew; Powell, David K.; Vandsburger, Moriel; Van Eldik, Linda J.; Abisambra, Jose F.

doi:10.1016/j.expneurol.2020.113180

Cited by 29Traumatic Brain Injury ResearchAlzheimer's disease research and treatmentsTraumatic Brain Injury and Neurovascular Disturbances

The effects of mild closed head injuries on tauopathy and cognitive deficits in rodents: Primary results in wild type and rTg4510 mice, and a systematic review

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Bachstetter, Adam D., Morganti, Josh M., Bodnar, Colleen N., Webster, Scott J., Higgins, Emma K., Roberts, Kelly N., Snider, Henry, Meier, Shelby E. +7 more·2020·Experimental Neurology

DOI 10.1016/j.expneurol.2020.113180PMC PMC7373372

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Abstract

In humans, the majority of sustained traumatic brain injuries (TBIs) are classified as 'mild' and most often a result of a closed head injury (CHI). The effects of a non-penetrating CHI are not benign and may lead to chronic pathology and behavioral dysfunction, which could be worsened by repeated head injury. Clinical-neuropathological correlation studies provide evidence that conversion of tau into abnormally phosphorylated proteotoxic intermediates (p-tau) could be part of the pathophysiology triggered by a single TBI and enhanced by repeated TBIs. However, the link between p-tau and CHI in rodents remains controversial. To address this question experimentally, we induced a single CHI or two CHIs to WT or rTg4510 mice. We found that 2× CHI increased tau phosphorylation in WT mice and rTg4510 mice. Behavioral characterization in WT mice found chronic deficits in the radial arm water maze in 2× CHI mice that had partially resolved in the 1× CHI mice. Moreover, using Manganese-Enhanced Magnetic Resonance Imaging with R1 mapping - a novel functional neuroimaging technique - we found greater deficits in the rTg4510 mice following 2× CHI compared to 1× CHI. To integrate our findings with prior work in the field, we conducted a systematic review of rodent mild repetitive CHI studies. Following Prisma guidelines, we identified 25 original peer-reviewed papers. Results from our experiments, as well as our systematic review, provide compelling evidence that tau phosphorylation is modified by experimental mild TBI studies; however, changes in p-tau levels are not universally reported. Together, our results provide evidence that repetitive TBIs can result in worse and more persistent neurological deficits compared to a single TBI, but the direct link between the worsened outcome and elevated p-tau could not be established.

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There is emerging evidence that repeated mTBI may confer additional risk for both persisting symptoms and cognitive compromise.
“There is emerging evidence that repeated mTBI may confer additional risk for both persisting symptoms and cognitive compromise.”
From Can mild traumatic brain injury alter cognition chronically? A LIMBIC-CENC multicenter study. (2023) · cites this paper as Bachstetter et al., 2020

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Authors: Bachstetter, A. D., Morganti, J. M., Bodnar, C. N., Webster, S. J., Higgins, E. K., Roberts, K. N., Snider, H., Meier, S. E., Nation, G. K., Goulding, D. S., Hamm, M., Powell, D. K., Vandsburger, M., Van Eldik, L. J., & Abisambra, J. F.
Affiliations: University of Kentucky HealthCare (US)
University of Kentucky (US)
University of Florida (US)
University of California, Berkeley (US)
Corresponding author: Bachstetter, Adam D.
Abisambra, Jose F.
ORCID: Bachstetter, Adam D.
Morganti, Josh M.
Snider, Henry
Meier, Shelby E.
Hamm, Matthew
Powell, David K.
Vandsburger, Moriel
Abisambra, Jose F.
Venue: Experimental Neurology
Publisher: Elsevier BV
Published: 2020-04
Volume: 326
Pages: 113180
ISSN: 0014-4886 (ISSN-L)
DOI: 10.1016/j.expneurol.2020.113180
PMC: PMC7373372
OpenAlex: W2999370828
Cited by: 29
References: 63
Citations by year: 2026: 3 · 2025: 4 · 2024: 3 · 2023: 4 · 2022: 7 · 2021: 5 · 2020: 3
FWCI: 0.69
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor, 78 d)
Locations: Experimental Neurology (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: U.S. Department of Defense (AZ140097)
National Institutes of Health (S10 RR029541, R01 NS091329, P30 AG028383, P30 GM110787, R01 NS103785, R00 AG044445, L32 MD009205, UL1 TR000117)
Topics: Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
Keywords: mild traumatic brain injury, closed head injury, tau phosphorylation, tauopathy, rTg4510 mice, repetitive head injury, cognitive impairment, radial arm water maze, manganese-enhanced MRI, R1 mapping
MeSH terms: Animals, Cognition Disorders, Mice, Neurologic Mutants, Head Injuries, Closed, Tauopathies, Mice

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The effects of mild closed head injuries on tauopathy and cognitive deficits in rodents: Primary results in wild type and rTg4510 mice, and a systematic review

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