There is an association between repetitive head injury (RHI) and a pathologic diagnosis of chronic traumatic encephalopathy (CTE) characterized by the aggregation of proteins including tau. The underlying molecular events that cause these abnormal protein accumulations remain unclear. Here, we hypothesized that identifying the human brain proteome from serial CTE stages (CTE I-IV) would provide critical new insights into CTE pathogenesis. Brain samples from frontotemporal lobar degeneration due to microtubule associated protein tau (FTLD-MAPT) mutations were also included as a distinct tauopathy phenotype for comparison. Isobaric tandem mass tagged labeling and mass spectrometry (TMT-MS) followed by integrated differential and co-expression analysis (i.e., weighted gene co-expression network analysis (WGCNA)) was used to define modules of highly correlated proteins associated with clinical and pathological phenotypes in control (n = 23), CTE (n = 43), and FTLD-MAPT (n = 12) post-mortem cortical tissues. We also compared these findings to network analysis of AD brain. We identified over 6000 unique proteins across all four CTE stages which sorted into 28 WGCNA modules. Consistent with Alzheimer’s disease, specific modules demonstrated reduced neuronal protein levels, suggesting a neurodegeneration phenotype, while other modules were increased, including proteins associated with inflammation and glial cell proliferation. Notably, unique CTE-specific modules demonstrated prominent enrichment of immunoglobulins, including IGHM and IGLL5, and extracellular matrix (ECM) proteins as well as progressive protein changes with increasing CTE pathologic stage. Finally, aggregate cell subtype (i.e., neurons, microglia, astrocytes) protein abundance levels in CTE cases were similar in expression to AD, but at intermediate levels between controls and the more exaggerated phenotype of FTLD-MAPT, especially in astrocytes. Overall, we identified thousands of protein changes in CTE postmortem brain and demonstrated that CTE has a pattern of neurodegeneration in neuronal-synaptic and inflammation modules similar to AD. We also identified unique CTE progressive changes, including the enrichment of immunoglobulins and ECM proteins even in early CTE stages. Early and sustained changes in astrocyte modules were also observed. Overall, the prominent overlap with FTLD-MAPT cases confirmed that CTE is on the tauopathy continuum and identified CTE stage specific molecular phenotypes that provide novel insights into disease pathogenesis.

中文翻译：

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蛋白质组学网络方法解决慢性创伤性脑病的阶段特异性分子表型

重复性头部损伤 (RHI) 与慢性创伤性脑病 (CTE) 的病理诊断之间存在关联，其特征是包括 tau 在内的蛋白质聚集。导致这些异常蛋白质积累的潜在分子事件仍不清楚。在这里，我们假设从连续 CTE 阶段 (CTE I-IV) 识别人脑蛋白质组将为 CTE 发病机制提供重要的新见解。由于微管相关蛋白 tau (FTLD-MAPT) 突变引起的额颞叶变性的脑样本也被包括作为一个独特的 tauopathy 表型进行比较。等压串联质谱标记和质谱（TMT-MS），然后进行综合差异和共表达分析（即，加权基因共表达网络分析 (WGCNA)) 用于定义与对照 (n = 23)、CTE (n = 43) 和 FTLD-MAPT (n = 12) 中的临床和病理表型相关的高度相关蛋白模块死后皮质组织。我们还将这些发现与 AD 大脑的网络分析进行了比较。我们在所有四个 CTE 阶段鉴定了 6000 多种独特的蛋白质，这些蛋白质分为 28 个 WGCNA 模块。与阿尔茨海默病一致，特定模块显示神经元蛋白水平降低，表明存在神经变性表型，而其他模块增加，包括与炎症和神经胶质细胞增殖相关的蛋白质。值得注意的是，独特的 CTE 特异性模块显示了免疫球蛋白的显着富集，包括 IGHM 和 IGLL5，和细胞外基质 (ECM) 蛋白以及进行性蛋白随着 CTE 病理阶段的增加而变化。最后，CTE 病例中的聚合细胞亚型（即神经元、小胶质细胞、星形胶质细胞）蛋白丰度水平在表达上与 AD 相似，但在对照和更夸张的 FTLD-MAPT 表型之间处于中间水平，尤其是在星形胶质细胞中。总体而言，我们在 CTE 死后大脑中发现了数千种蛋白质变化，并证明 CTE 在神经元突触和炎症模块中具有类似于 AD 的神经变性模式。我们还发现了独特的 CTE 进行性变化，包括免疫球蛋白和 ECM 蛋白的富集，即使在早期 CTE 阶段也是如此。还观察到星形胶质细胞模块的早期和持续变化。总体，