Proteomic Profiling of Extracellular Vesicles Isolated From Cerebrospinal Fluid of Former National Football League Players at Risk for Chronic Traumatic Encephalopathy

• Published in: Frontiers in neuroscience Vol. 13; p. 1059
• Main Authors: Muraoka, Satoshi, Jedrychowski, Mark P, Tatebe, Harutsugu, DeLeo, Annina M, Ikezu, Seiko, Tokuda, Takahiko, Gygi, Steven P, Stern, Robert A, Ikezu, Tsuneya
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 09.10.2019; Frontiers Media S.A
• Subjects: Astrocytes; Biomarkers; Cerebrospinal fluid; Chronic traumatic encephalopathy; Cognitive ability; Concussion; Cortex; Disease; Disease spread; Encephalopathy; Extracellular vesicles; Fluids; Football; Immunoassay; Liver X receptors; Medicine; Mental disorders; MicroRNAs; microtubule-associated protein tau; Neurodegeneration; Neurodegenerative diseases; Neurofibrillary tangles; Neuropathology; Neuroscience; Neurosciences; Pathology; Protein composition; Proteins; proteome; Receptor mechanisms; Tau protein; tauopathy; Traumatic brain injury; United States > US; Japan; tauopathy; extracellular vesicles; microtubule-associated protein tau; cerebrospinal fluid; football; chronic traumatic encephalopathy; proteome
• ISSN: 1662-4548; 1662-453X; 1662-453X
• DOI: 10.3389/fnins.2019.01059

Chronic Traumatic Encephalopathy (CTE) is a tauopathy that affects individuals with a history of repetitive mild traumatic brain injury, such as American football players. Initial neuropathologic changes in CTE include perivascular deposition of phosphorylated microtubule-associated protein tau (p-tau) neurofibrillary tangles and other aggregates in neurons, astrocytes and cell processes in an irregular pattern often at the depths of the cortical sulci. In later stages, the p-tau depositions become widespread and is associated with neurodegeneration. Extracellular vesicles (EVs) are known to carry neuropathogenic molecules, most notably p-tau. We therefore examined the protein composition of EVs isolated from the cerebrospinal fluid (CSF) of former National Football League (NFL) players with cognitive and neuropsychiatric dysfunction, and an age-matched control group (CTRL) with no history of contact sports or traumatic brain injury. EVs were isolated from the CSF samples using an affinity purification kit. Total tau (t-tau) and tau phosphorylated on threonine181 (p-tau ) in CSF-derived EVs from former NFL players and CTRL participants were measured by ultrasensitive immunoassay. The t-tau and p-tau levels of CSF-derived EV were positively correlated with the t-tau and p-tau levels of total CSF in former NFL players, respectively, but not in the CTRL group. 429 unique proteins were identified from CSF-derived EVs and quantified by TMT-10 plex method. The identified protein molecules were significantly enriched for the extracellular exosome molecules, Alzheimer's disease pathway and Age/Telomere Length ontology as determined by DAVID Gene Ontology analysis. Ingenuity pathway analysis of the differentially expressed EV proteins revealed enrichment of canonical liver/retinoid X receptor activation pathway. Upstream effect analysis predicted MAPT (tau) as an upstream regulator in former NFL players. These data will be useful for understanding the EV-mediated disease spread and development of novel EV biomarkers for CTE and related disorders.