期刊
JOURNAL OF ALZHEIMERS DISEASE
卷 64, 期 3, 页码 709-722出版社
IOS PRESS
DOI: 10.3233/JAD-180177
关键词
3xTg-AD mice; asparaginyl endopeptidase; chronic traumatic encephalopathy; tau hyperphosphorylation; traumatic brain injury
资金
- New York State Office for People with Developmental Disabilities (OPWDD)
- Alzheimer's Association, USA [ZEN-120241433, DSAD-15-363172, 2016-NIRG-397030]
- National Natural Science Foundation of China [31671046, 81773713]
Traumatic brain injury (TBI) is an established risk factor for the development of neurodegeneration and dementia late in life. Repetitive mild TBI (r-mTBI) is directly associated with chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disorder characterized by focal perivascular to widespread Alzheimer-type neurofibrillary pathology of hyperphosphorylated tau. Studies in animal models have shown hyperphosphorylation of tau after TBI. However, the molecular mechanisms by which TBI leads to tau pathology are not understood. In this study, we employed western blots and immunohistochemistry to test, in triple-transgenic mouse model of Alzheimer's disease (3xTg-AD), the effect of r-mTBI on tau hyperphosphorylation and activation of asparaginyl endopeptidase (AEP), a cysteine proteinase which is known to be involved in tau hyperphosphorylation. We found that the level of active AEP was increased and correlated with the level of tau hyperphosphorylation following r-mTBI, and that fimbria showed increased immunoreactivity to phospho-tau. In addition, inhibitor 2 of protein phosphatase 2A (I-2(PP2A)) was translocated from neuronal nucleus to the cytoplasm and colocalized with hyperphosphorylated tau. These data suggest the involvement of AEP-I-2(PP2A)-PP2A-ptau pathway in tau pathology in TBI.
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