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.

Keywords: American football; CTE; Microglia; Mild traumatic brain injury; Neuroinflammation; Repetitive head impacts.

Fig. 1

Glial morphology, but not overall cell number, changes during CTE pathological stage progression. a-c Quantification of the total number of Iba1 positive (a), GFAP positive (b), and CD68 positive cells present at the depths of the sulci in the dorsolateral frontal cortex. d Representative images at 10× (d) and 63× (e) magnification of Iba1 depicting the morphologic change of microglia into activated, reactive morphology (arrows). f Representative image of Iba1 immunoreacive microglia surrounding clusters of AT8 immunoreactive cells. White arrows denote Iba1 cell body near AT8 aggregates. Blue arrow denotes microglia process contacting AT8 immunoreactive neuron. Data displayed as mean ± SEM, scale bars represent 300 μm (d) and 50 μm (e,f), *p ≤ 0.05, **p ≤ 0.01

Fig. 2

Pathway analysis of CTE associated variables. Visual representation of significant interactions from the simultaneous equation regression analysis. Rectangles represent predictor variables while circles represent outcome variables. Arrows denote a significant direct effect

Fig. 3

A model of the progression of neuroinflammation, ptau pathology, and probability of developing dementia in CTE. The regression lines for CD68 cell density, NFT density, and the probability of developing dementia were plotted within a single graph and correlated with time from first exposure to death (years). Binary logistic regression beta values were used to generate the probability curve for dementia