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Evaluation of extracellular vesicles isolated from the cerebrospinal fluid and plasma from former National Football League players at risk for chronic traumatic encephalopathy
Author(s) -
Muraoka Satoshi,
Jedrychowski Mark P.,
Yang Zijian,
Tatebe Harutsugu,
DeLeo Annina M.,
Yukawa Kayo,
Ko Jina,
Wang Katherine,
Ikezu Seiko,
Gygi Steven,
Issadore David,
Tokuda Takahiko,
Stern Robert A,
Ikezu Tsuneya
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.042233
Subject(s) - chronic traumatic encephalopathy , tauopathy , cerebrospinal fluid , tau protein , traumatic brain injury , concussion , extracellular vesicle , chemistry , medicine , pathology , psychology , endocrinology , disease , alzheimer's disease , neurodegeneration , psychiatry , biochemistry , poison control , microvesicles , gene , microrna , environmental health , injury prevention
Background Chronic Traumatic Encephalopathy (CTE) is a tauopathy that affects individuals with a history of mild repetitive brain injury frequently seen in contact sports. Initial neuropathologic change of CTE consists of perivascular deposition of phosphorylated tau (p‐tau) in cortical neurons. Tau pathology progresses to form neurofibrillary tangles in neurons throughout the brain in later stages when patients show more clinical symptoms. Extracellular vesicles (EV) are known to carry neuropathogenic molecules in neurodegenerative disease and able to cross the blood brain barrier. We therefore examined the protein composition of EV separated from cerebrospinal fluid (CSF) and plasma in former NFL players with cognitive dysfunction, and an age‐matched controls. Method EVs were separated from CSF and plasma from former NFL players (n=4, 14) and controls (n=5, 12) by affinity separation or size exclusion chromatography, respectively. The EV protein profiling was characterized by SIMOA for tau and p‐tau and mass spectrometry. The protein data was analyzed for EV enrichment, differentially expressed proteins, pathway analysis and correlation with cognitive function, head impact and tau/p‐tau levels by biostatistics and bioinformatics. Result The level of t‐tau and p‐tau in plasma EVs from former NFL players was significantly elevated although there was no significant change in CSF EV compared to the control. The 95 proteins were commonly identified between the paired plasma‐CSF from the same patients, but there was no significant correlation with the disease status. Collagen alpha‐3(VI) chain (COL6A3), ‐1(VI) chain (COL6A1) and Reelin (RELN) were differentially expressed in former NFL players’ plasma EVs. A combination of these 3 proteins in plasma EV was able to distinguish former NFL players from controls with 85% accuracy by machine learning. Conclusion These data suggest that COL6A3, RELN and COL6A1 in plasma EV can be potential biomarker for monitoring the CTE development. We need further evaluation of CSF EV by increasing the sample number size in future studies.