Repetitive Mild Brain Trauma Accelerates Aβ Deposition, Lipid Peroxidation, and Cognitive Impairment in a Transgenic Mouse Model of Alzheimer Amyloidosis
Open accessAbstract
Traumatic brain injury (TBI) increases susceptibility to Alzheimer's disease (AD), but it is not known how TBI contributes to the onset or progression of this common late life dementia. To address this question, we studied neuropathological and behavioral consequences of single versus repetitive mild TBI (mTBI) in transgenic (Tg) mice (Tg2576) that express mutant human Abeta precursor protein, and we demonstrate elevated brain Abeta levels and increased Abeta deposition. Nine-month-old Tg2576 and wild-type mice were subjected to single (n = 15) or repetitive (n = 39) mTBI or sham treatment (n = 37). At 2 d and 9 and 16 weeks after treatment, we assessed brain Abeta deposits and levels in addition to brain and urine isoprostanes generated by lipid peroxidation in these mice. A subset of mice also was studied behaviorally at 16 weeks after injury. Repetitive but not single mTBI increased Abeta deposition as well as levels of Abeta and isoprostanes only in Tg mice, and repetitive mTBI alone induced cognitive impairments but no motor deficits in these mice. This is the first experimental evidence linking TBI to mechanisms of AD by showing that repetitive TBI accelerates brain Abeta accumulation and oxidative stress, which we suggest could work synergistically to promote the onset or drive the progression of AD. Additional insights into the role of TBI in mechanisms of AD pathobiology could lead to strategies for reducing the risk of AD associated with previous episodes of brain trauma and for preventing progressive brain amyloidosis in AD patients.
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The rapid accumulation of Aβ after TBI is well documented in both humans and experimental animal models.
“The rapid accumulation of Aβ after TBI is well documented in both humans and experimental animal models.12–17”
From Controlled Cortical Impact Results in an Extensive Loss of Dendritic Spines that Is Not Mediated by Injury-Induced Amyloid-Beta Accumulation (2013) · cites this paper as [17]
The Discussion reports Aβ deposits in deceased acute human head-trauma victims and accelerated Aβ deposition in this transgenic mouse model. However, the Amyloid deposition section reports a significant increase in mice only at 16 weeks after injury, not rapid accumulation, and the Discussion says earlier animal-model studies did not show a similar association. Thus the claim overstates how well rapid accumulation is documented across both groups. (LLM, conf=0.89)
Experimental — accuracy not yet measuredOnly two reports examining repetitive TBI in Tg2576 mice showed increased Aβ in addition to behavioral impairment at chronic post-injury time points.
“Only two reports examining repetitive TBI in Tg2576 mice showed increased Aβ in addition to behavioral impairment at chronic post-injury time points (165, 233).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [165]
Single TBI induces acute tau phosphorylation but not aggregation.
“Together, these studies demonstrate that single TBI induces acute tau phosphorylation but not aggregation.”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [165]
The Histology and Discussion passages address single mild TBI in terms of tissue pathology, amyloid deposition, and lipid peroxidation, but do not report tau phosphorylation or aggregation. Searches for tau phosphorylation and neurofibrillary tangles found only a general mention of tangles as an Alzheimer’s disease hallmark, not a finding after single TBI. Page numbers were unavailable in our copy. (LLM, conf=0.76)
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References 64 · Cited by 337
- Authors
- Uryu, K., Laurer, H., McIntosh, T., Praticò, D., Martinez, D., Leight, S., Lee, V. M.-Y., & Trojanowski, J. Q.
- Affiliations
- University of Pennsylvania (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2002-01-15
- Volume
- 22
- Issue
- 2
- Pages
- 446-454
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6758680
- OpenAlex
- W2153945143
- Cited by
- 337
- References
- 64
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 10 · 2023: 8 · 2022: 5 · 2021: 10 · 2020: 14 · 2019: 12 · 2018: 13 · 2017: 17 · 2016: 16 · 2015: 24 · 2014: 19 · 2013: 23 · 2012: 19
- FWCI
- 13.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (NS08803)
- National Institute of Neurological Disorders and Stroke (P50 NS08803, P50NS008803)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- repetitive mild traumatic brain injury, Alzheimer's disease, amyloid-beta deposition, Tg2576 mice, isoprostanes, lipid peroxidation, oxidative stress, cognitive impairment, motor impairment, cerebral amyloidosis
- MeSH terms
- Alzheimer Disease, Amyloidosis, Animals, Behavior, Animal, Brain, Brain Injuries, Cognition Disorders, Disease Models, Animal, Disease Susceptibility, Female, Glial Fibrillary Acidic Protein, Humans, Male, Mice, Transgenic, Motor Activity, Neurologic Examination, Reaction Time, Lipid Peroxidation, Biomarkers, Amyloid beta-Peptides, Head Injuries, Closed, Amyloid beta-Protein Precursor, Disease Progression, Isoprostanes, Mice
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