A proteomic network approach resolves stage-specific molecular phenotypes in chronic traumatic encephalopathy

Background 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. Methods 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. Results 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. Conclusions 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.