Abstract
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-tau181) in CSF-derived EVs from former NFL players and CTRL participants were measured by ultrasensitive immunoassay. The t-tau and p-tau181 levels of CSF-derived EV were positively correlated with the t-tau and p-tau181 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.
Highlights
Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive mild traumatic brain injury, including concussion and subconcussion
The Extracellular vesicles (EVs) were isolated from former National Football League (NFL) players Cerebrospinal fluid (CSF) and an age-matched control group (CTRL) with no history of contact sports or traumatic brain injury using the MagCapture Exosome isolation kit
We found that t-tau and p-tau181 levels of CSF-derived EV were positively correlated with the t-tau and p-tau181 levels of total CSF in former NFL players, but not in the CTRL group
Summary
Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive mild traumatic brain injury, including concussion and subconcussion. CTE was first described in boxers in the 1920s and 1930s as “punch drunk,” (Martland, 1928) or “dementia pugilistica,” (Millspaugh, 1937) but has been more recently identified in other contact/collision sports athletes (including American football, soccer, ice hockey, and rugby players) (McKee et al, 2013, 2016; Bieniek et al, 2015; Ling et al, 2017; Mez et al, 2017; Tagge et al, 2018). Similar to other neurodegenerative diseases, CTE can only be diagnosed conclusively by neuropathologic examination. It is characterized by the 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. CTE has a unique neuropathology from other tauopathies and the tau filaments of CTE are distinct from those in Alzheimer’s disease (AD) (McKee et al, 2016; Falcon et al, 2019)
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