Abstract
BackgroundNeuroinflammation has been implicated in the pathogenesis of chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disease association with exposure to repetitive head impacts (RHI) received though playing contact sports such as American football. Past work has implicated early and sustained activation of microglia as a potential driver of tau pathology within the frontal cortex in CTE. However, the RHI induced signals required to recruit microglia to areas of damage and pathology are unknown.MethodsPostmortem brain tissue was obtained from 261 individuals across multiple brain banks. Comparisons were made using cases with CTE, cases with Alzheimer’s disease (AD), and cases with no neurodegenerative disease and lacked exposure to RHI (controls). Recruitment of Iba1+ cells around the CTE perivascular lesion was compared to non-lesion vessels. TMEM119 staining was used to characterize microglia or macrophage involvement. The potent chemoattractant CCL2 was analyzed using frozen tissue from the dorsolateral frontal cortex (DLFC) and the calcarine cortex. Finally, the amounts of hyperphosphorylated tau (pTau) and Aβ42 were compared to CCL2 levels to examine possible mechanistic pathways.ResultsAn increase in Iba1+ cells was found around blood vessels with perivascular tau pathology compared to non-affected vessels in individuals with RHI. TMEM119 staining revealed the majority of the Iba1+ cells were microglia. CCL2 protein levels in the DLFC were found to correlate with greater years of playing American football, the density of Iba1+ cells, the density of CD68+ cells, and increased CTE severity. When comparing across multiple brain regions, CCL2 increases were more pronounced in the DLFC than the calcarine cortex in cases with RHI but not in AD. When examining the individual contribution of pathogenic proteins to CCL2 changes, pTau correlated with CCL2, independent of age at death and Aβ42 in AD and CTE. Although levels of Aβ42 were not correlated with CCL2 in cases with CTE, in males in the AD group, Aβ42 trended toward an inverse relationship with CCL2 suggesting possible gender associations.ConclusionOverall, CCL2 is implicated in the pathways recruiting microglia and the development of pTau pathology after exposure to RHI, and may represent a future therapeutic target in CTE.
Highlights
Neuroinflammation has been implicated in the pathogenesis of chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disease association with exposure to repetitive head impacts (RHI) received though playing contact sports such as American football
The CTE pathognomonic lesion recruits Iba1+ cells To determine if the pathology found in CTE was directly related to increased glial cell recruitment, the Iba1+ cell density directly around blood vessels that presented with phosphorylated tau (pTau) pathology was compared to neighboring blood vessels in the same tissue without pTau pathology (Fig. 1)
Analysis of the specific effect of pTau and Aβ42 demonstrated that pTau correlated with C-C Motif chemokine ligand 2 (CCL2) in both Alzheimer’s disease (AD) and CTE cases
Summary
Neuroinflammation has been implicated in the pathogenesis of chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disease association with exposure to repetitive head impacts (RHI) received though playing contact sports such as American football. The RHI induced signals required to recruit microglia to areas of damage and pathology are unknown. One important facet of the inflammatory response is the signaling cascades used to bring inflammatory cells to the areas of damage or pathology (i.e., chemokines). Similar inflammatory cell recruitment responses can be observed across distinct injuries. Microglia recruitment around Aβ plaques in Alzheimer’s disease (AD) are commonly observed. In both CTE and AD, chronic signaling through repetitive injuries or failure to remove toxic protein products is hypothesized to result in constant recruitment of inflammatory microglia/macrophage and may perpetuate a chronic neuroinflammatory response and disease propagation
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