Microglial neuroinflammation contributes to tau accumulation in chronic traumatic encephalopathy

Abstract

The chronic effects of repetitive head impacts (RHI) on the development of neuroinflammation and its relationship to chronic traumatic encephalopathy (CTE) are unknown. Here we set out to determine the relationship between RHI exposure, neuroinflammation, and the development of hyperphosphorylated tau (ptau) pathology and dementia risk in CTE. We studied a cohort of 66 deceased American football athletes from the Boston University-Veteran’s Affairs-Concussion Legacy Foundation Brain Bank as well as 16 non-athlete controls. Subjects with a neurodegenerative disease other than CTE were excluded. Counts of total and activated microglia, astrocytes, and ptau pathology were performed in the dorsolateral frontal cortex (DLF). Binary logistic and simultaneous equation regression models were used to test associations between RHI exposure, microglia, ptau pathology, and dementia. Duration of RHI exposure and the development and severity of CTE were associated with reactive microglial morphology and increased numbers of CD68 immunoreactive microglia in the DLF. A simultaneous equation regression model demonstrated that RHI exposure had a significant direct effect on CD68 cell density (p < 0.0001) and ptau pathology (p < 0.0001) independent of age at death. The effect of RHI on ptau pathology was partially mediated through increased CD68 positive cell density. A binary logistic regression demonstrated that a diagnosis of dementia was significantly predicted by CD68 cell density (OR = 1.010, p = 0.011) independent of age (OR = 1.055, p = 0.007), but this effect disappeared when ptau pathology was included in the model. In conclusion, RHI is associated with chronic activation of microglia, which may partially mediate the effect of RHI on the development of ptau pathology and dementia in CTE. Inflammatory molecules may be important diagnostic or predictive biomarkers as well as promising therapeutic targets in CTE.

Age of first exposure to tackle football and chronic traumatic encephalopathy

“…44,45 RHI intensity and duration and their interaction with variables like age and genetics (e.g., APOE e4 ) 3,7 may be more important determinants of pathology. 3,39 In contrast, our findings that show a relationship between AFE and age of symptom onset are consistent with previous research in living former amateur and professional tackle football players that linked younger AFE to tackle football, before age 12 in particular, with worse cognitive, behavior, and mood outcomes. 11,14 The clinical presentation of CTE seems to involve early-life behavioral/mood symptoms and/or later-life cognitive impairment.…”

Neuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift

“…This is further supported by recent in vivo brain imaging studies of football athletes, which revealed evidence of chronic microglial activation (Cherry et al, 2016; Coughlin et al, 2017). Interestingly, research in murine AD models has shown that neuroinflammatory cytokines and reactive microglia can promote tau pathology and contribute to the spread of pTau, which might explain the link between TBI-induced inflammation and CTE (Ghosh et al, 2013; Maphis et al, 2015).…”

A Brief Overview of Tauopathy: Causes, Consequences, and Therapeutic Strategies

“…Second, injury-induced severing of neuronal axons may cause tau to dissociate from microtubules, which could facilitate subsequent tau aggregation [35]. Third, the chronic inflammation that results from brain injuries likely exacerbates and sustains the acute tauopathy that occurs shortly after injury [36]. …”