CCL2 与慢性创伤性脑病中的小胶质细胞和巨噬细胞募集有关。
CCL2 is associated with microglia and macrophage recruitment in chronic traumatic encephalopathy.
机构信息
Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA.
Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
出版信息
J Neuroinflammation. 2020 Dec 5;17(1):370. doi: 10.1186/s12974-020-02036-4.
BACKGROUND
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. 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.
METHODS
Postmortem 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 Aβ were compared to CCL2 levels to examine possible mechanistic pathways.
RESULTS
An 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 Aβ in AD and CTE. Although levels of Aβ were not correlated with CCL2 in cases with CTE, in males in the AD group, Aβ trended toward an inverse relationship with CCL2 suggesting possible gender associations.
CONCLUSION
Overall, 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.
背景
神经炎症与慢性创伤性脑病（CTE）的发病机制有关，CTE 是一种与接触性运动（如美式橄榄球）中的重复性头部撞击（RHI）有关的进行性神经退行性疾病。过去的研究表明，小胶质细胞的早期和持续激活可能是 CTE 额皮质中 tau 病理的潜在驱动因素。然而，招募小胶质细胞到损伤和病变区域所需的 RHI 诱导信号尚不清楚。
方法
从多个脑库中获得了 261 个人的死后脑组织。使用 CTE 病例、阿尔茨海默病（AD）病例和无神经退行性疾病且无 RHI 暴露（对照组）的病例进行了比较。比较了 CTE 血管周围病变周围的 Iba1+细胞的募集情况与非病变血管。使用来自背外侧额皮质（DLFC）和距状皮质的冷冻组织分析 TMEM119 染色以表征小胶质细胞或巨噬细胞的参与情况。使用 DLFC 和距状皮质的冷冻组织分析趋化因子 CCL2 的含量。最后，将 CCL2 水平与过度磷酸化 tau（pTau）和 Aβ进行比较，以研究可能的机制途径。
结果
与未受影响的血管相比，在有 RHI 的个体中，血管周围有 tau 病理的血管周围发现 Iba1+细胞增加。TMEM119 染色显示大多数 Iba1+细胞是小胶质细胞。在 DLFC 中发现 CCL2 蛋白水平与更多年的美式橄榄球比赛、Iba1+细胞密度、CD68+细胞密度和 CTE 严重程度的增加相关。当比较多个脑区时，在有 RHI 的病例中，与距状皮质相比，DLFC 中的 CCL2 增加更为明显，但在 AD 中则不然。当检查致病性蛋白对 CCL2 变化的个体贡献时，pTau 与 CCL2 相关，与 AD 和 CTE 中的死亡年龄和 Aβ无关。尽管在 CTE 病例中，Aβ 与 CCL2 不相关，但在 AD 组的男性中，Aβ 与 CCL2 呈负相关趋势，表明可能存在性别关联。
结论
总的来说，CCL2 参与了招募小胶质细胞和 RHI 暴露后 pTau 病理的途径，可能是 CTE 的未来治疗靶点。
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