Long-term accumulation of amyloid-beta, beta-secretase, presenilin-1, and caspase-3 in damaged axons following brain trauma.
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.
Department of Neurosurgery, University of Pennsylvania, 105c Hayden Hall, 3320 SmithWalk, Philadelphia, PA 19104-6316, USA.
Xiao-Han
XH
Chen
Robert
R
Siman
Akira
A
Iwata
David F
DF
Meaney
John Q
JQ
Trojanowski
Douglas H
DH
Smith
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism*; D005260:Female; D007124:Immunoenzyme Techniques; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D053764:Presenilin-1; D013552:Swine
D016229:Amyloid beta-Peptides; D015415:Biomarkers; D008565:Membrane Proteins; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D053148:Caspase 3; D020169:Caspases; D016282:Aspartic Acid Endopeptidases