Apolipoprotein E4 influences amyloid deposition but not cell loss after traumatic brain injury in a mouse model of Alzheimer’s disease
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The epsilon4 allele of apolipoprotein E (APOE) and traumatic brain injury (TBI) are both risk factors for the development of Alzheimer's disease (AD). These factors may act synergistically, in that APOE4+ individuals are more likely to develop dementia after TBI. Because the mechanism underlying these effects is unclear, we questioned whether APOE4 and TBI interact either through effects on amyloid-beta (Abeta) or by enhancing cell death/tissue injury. We assessed the effects of TBI in PDAPP mice (transgenic mice that develop AD-like pathology) expressing human APOE3 (PDAPP:E3), human APOE4 (PDAPP:E4), or no APOE (PDAPP:E-/-). Mice were subjected to a unilateral cortical impact injury at 9-10 months of age and allowed to survive for 3 months. Abeta load, hippocampal/cortical volumes, and hippocampal CA3 cell loss were quantified using stereological methods. All of the groups contained mice with Abeta-immunoreactive deposits (56% PDAPP:E4, 20% PDAPP:E3, 75% PDAPP:E-/-), but thioflavine-S-positive Abeta (amyloid) was present only in the molecular layer of the dentate gyrus in the PDAPP:E4 mice (44%). In contrast, our previous studies showed that in the absence of TBI, PDAPP:E3 and PDAPP:E4 mice have little to no Abeta deposition at this age. After TBI, all of the Abeta deposits present in PDAPP:E3 and PDAPP:E-/- mice were diffuse plaques. In contrast to the effect of APOE4 on amyloid, PDAPP:E3, PDAPP:E4, and PDAPP:E-/- mice did not differ in the amount of brain tissue or cell loss. These data support the hypothesis that APOE4 influences the neurodegenerative cascade after TBI via an effect on Abeta.
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Many animal studies show increased production and accumulation of amyloid precursor protein (APP), Aβ, and pathological tau following TBI.
“Second, many animal studies show increased production and accumulation of amyloid precursor protein (APP), Aβ, and pathological tau following TBI (16, 21–28).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [27]
The Discussion reports that TBI accelerated Aβ deposition in the study’s PDAPP mice expressing APOE4 and describes Aβ findings from other animal studies. It does not report increased production or accumulation of APP or pathological tau after TBI; nor does it establish increased Aβ production. (LLM, conf=0.89)
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References 43 · Cited by 115
- Authors
- Hartman, R. E., Laurer, H., Longhi, L., Bales, K. R., Paul, S. M., McIntosh, T. K., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- University of Pennsylvania (US)
- Eli Lilly (United States) (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2002-12-01
- Volume
- 22
- Issue
- 23
- Pages
- 10083-10087
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6758744
- OpenAlex
- W2158713023
- Cited by
- 115
- References
- 43
- Citations by year
- 2026: 2 · 2025: 1 · 2023: 1 · 2022: 3 · 2021: 1 · 2020: 1 · 2019: 10 · 2018: 3 · 2017: 2 · 2016: 4 · 2015: 8 · 2014: 7 · 2013: 8 · 2012: 6
- FWCI
- 4.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by)
- Purdue University Indianapolis (Indiana University) (submittedVersion, cc-by)
- PMC
- Funders
- National Institutes of Health (NS08803, DA07261, AG05681, AG13956, AG11355)
- National Institute on Aging (AG11355, R01AG013956, AG 05681, P50AG005681, R37AG013956, AG13956, P01AG011355)
- National Institute on Drug Abuse (DA07261, T32DA007261)
- National Institute of Neurological Disorders and Stroke (P50NS008803, NS-08803)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Keywords
- APOE ε4, traumatic brain injury, Alzheimer's disease, amyloid-beta deposition, amyloid plaques, hippocampal neuronal loss, cortical impact injury, dentate gyrus, neurodegeneration
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Brain Injuries, Cell Count, Cerebral Cortex, Disease Models, Animal, Hippocampus, Humans, Mice, Transgenic, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Disease Progression, Dentate Gyrus, Mice, Apolipoprotein E3, Apolipoprotein E4
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