Multiple proteins implicated in neurodegenerative diseases accumulate in axons after brain trauma in humans.
Studies in animal models have shown that traumatic brain injury (TBI) induces the rapid accumulation of many of the same key proteins that form pathologic aggregates in neurodegenerative diseases. Here, we examined whether this rapid process also occurs in humans after TBI. Brain tissue from 18 cases who died after TBI and from 6 control cases was examined using immunohistochemistry. Following TBI, widespread axonal injury was persistently identified by the accumulation of neurofilament protein and amyloid precursor protein (APP) in axonal bulbs and varicosities. Axonal APP was found to co-accumulate with its cleavage enzymes, beta-site APP cleaving enzyme (BACE), presenilin-1 (PS1) and their product, amyloid-beta (Abeta). In addition, extensive accumulation of alpha-synuclein (alpha-syn) was found in swollen axons and tau protein was found to accumulate in both axons and neuronal cell bodies. These data show rapid axonal accumulation of proteins implicated in neurodegenerative diseases including Alzheimer's disease and the synucleinopathies. The cause of axonal pathology can be attributed to disruption of axons due to trauma, or as a secondary effect of raised intracranial pressure or hypoxia. Such axonal pathology in humans may provide a unique environment whereby co-accumulation of APP, BACE, and PS1 leads to intra-axonal production of Abeta as well as accumulation of alpha-syn and tau. This process may have important implications for survivors of TBI who have been shown to be at greater risk of developing neurodegenerative diseases.
Uryu
Kunihiro
K
The Center for Neurodegenerative Disease Research, Pathology and Laboratory Medicine, USA.
Chen
Xiao-Han
XH
Martinez
Dan
D
Browne
Kevin D
KD
Johnson
Victoria E
VE
Graham
David I
DI
Lee
Virginia M-Y
VM
Trojanowski
John Q
JQ
Smith
Douglas H
DH
D000293:Adolescent; D000328:Adult; D000368:Aged; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology; D002102:Cadaver; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D014018:Tissue Distribution