Long-Term Accumulation of Amyloid-β, β-Secretase, Presenilin-1, and Caspase-3 in Damaged Axons Following Brain Trauma

Chen, Xiao-Han; Siman, Robert; Iwata, Akira; Meaney, David F.; Trojanowski, John Q.; Smith, Douglas H.

doi:10.1016/s0002-9440(10)63303-2

Cited by 271Alzheimer's disease research and treatmentsTraumatic Brain Injury and Neurovascular DisturbancesTraumatic Brain Injury Research

Long-Term Accumulation of Amyloid-β, β-Secretase, Presenilin-1, and Caspase-3 in Damaged Axons Following Brain Trauma

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Chen, Xiao-Han, Siman, Robert, Iwata, Akira, Meaney, David F., Trojanowski, John Q., Smith, Douglas H.·2004·The American Journal of Pathology

DOI 10.1016/s0002-9440(10)63303-2PMC PMC1618579

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Abstract

Plaques composed of amyloid beta (Abeta) have been found within days following brain trauma in humans, similar to the hallmark plaque pathology of Alzheimer's disease (AD). Here, we evaluated the potential source of this Abeta and long-term mechanisms that could lead to its production. Inertial brain injury was induced in pigs via head rotational acceleration of 110 degrees over 20 ms in the coronal plane. Animals were euthanized at 3 hours, 3 days, 7 days, and 6 months post-injury. Immunohistochemistry and Western blot analyses of the brains were performed using antibodies specific for amyloid precursor protein (APP), Abeta peptides, beta-site APP-cleaving enzyme (BACE), presenilin-1 (PS-1), caspase-3, and caspase-mediated cleavage of APP (CCA). Substantial co-accumulation for all of these factors was found in swollen axons at all time points up to 6 months following injury. Western blot analysis of injured brains confirmed a substantial increase in the protein levels of these factors, particularly in the white matter. These data suggest that impaired axonal transport due to trauma induces long-term pathological co-accumulation of APP with BACE, PS-1, and activated caspase. The abnormal concentration of these factors may lead to APP proteolysis and Abeta formation within the axonal membrane compartment.

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Aβ deposition is apparent following rotational acceleration TBI in pigs and rabbits.
“Although Aβ deposition is apparent following rotational acceleration TBI in pigs (132, 133) and rabbits (134)”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [133]
Stress and resultant axonal injury are greatest at the interface of two tissues with differing viscoelastic properties, and the depths of cortical sulci are areas of stress concentration.
“Stress and resultant axonal injury are greatest at the interface of two tissues with differing viscoelastic properties (such as between blood vessels and brain, or between gray and white matter) and the depths of the cortical sulci are areas of stress concentration [11, 28, 33].”
From The neuropathology of sport (2014) · cites this paper as [28]
The patchy, perivascular location of PHF-tau pathology in sulcal depths, prominent in early CTE, is most likely related to the physics of traumatic injury and shear deformation of the brain.
“The patchy, perivascular location of the PHF-tau pathology in sulcal depths, features prominent in early CTE, is most likely related to the physics of traumatic injury and shear deformation of the brain.”
From The neuropathology of sport (2014) · cites this paper as [28]

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Authors: Chen, X.-H., Siman, R., Iwata, A., Meaney, D. F., Trojanowski, J. Q., & Smith, D. H.
Affiliations: University of Pennsylvania (US)
Corresponding author: Smith, Douglas H.
ORCID: Iwata, Akira
Meaney, David F.
Trojanowski, John Q.
Smith, Douglas H.
Venue: The American Journal of Pathology
Publisher: Elsevier BV
Published: 2004-08
Volume: 165
Issue: 2
Pages: 357-371
ISSN: 0002-9440 (ISSN-L)
DOI: 10.1016/s0002-9440(10)63303-2
PMC: PMC1618579
OpenAlex: W1965918817
Cited by: 271
References: 85
Citations by year: 2026: 3 · 2025: 8 · 2024: 11 · 2023: 12 · 2022: 9 · 2021: 16 · 2020: 11 · 2019: 17 · 2018: 11 · 2017: 9 · 2016: 20 · 2015: 16 · 2014: 15 · 2013: 19 · 2012: 22
FWCI: 5.98
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: American Journal Of Pathology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (AG11542, NS38104, NS08803)
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: amyloid-beta, beta-secretase, presenilin 1, caspase-3, amyloid precursor protein, traumatic brain injury, axonal transport, axonal swellings, white matter, APP proteolysis, Alzheimer's disease pathology, pigs
MeSH terms: Animals, Axons, Brain, Brain Injuries, Female, Immunoenzyme Techniques, Male, Membrane Proteins, Neurons, Endopeptidases, Swine, Blotting, Western, Biomarkers, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Caspases, Caspase 3, Presenilin-1, Amyloid Precursor Protein Secretases

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Long-Term Accumulation of Amyloid-β, β-Secretase, Presenilin-1, and Caspase-3 in Damaged Axons Following Brain Trauma

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