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

• Type of Material: Article
• Authors: Laura Gutierrez-Quiceno, Emory University; Eric Dammer, Emory University; Ashlyn G Johnson, Emory University; James A Webster, Emory University; Rhythm Shah, Emory University; Duc Duong, Emory University; Luming Yin, Emory University; Nicholas Seyfried, Emory University; Victor E Alvarez, Boston University; Thor D Stein, Boston University; Ann C McKee, Boston University; Chadwick Hales, Emory University
• Language: English
• Date: 2021-06-25
• Publisher: BMC
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13024-021-00462-3
• Title of Journal or Parent Work: MOLECULAR NEURODEGENERATION
• Volume: 16
• Issue: 1
• Start Page: 40
• End Page: 40
• Grant/Funding Information: This work was supported by the Department of Veterans Affairs, Veterans Health Administration, Clinical Sciences Research and Development Merit Award (I01-CX001038) to TDS; Veterans Affairs Biorepository (CSP 501) to TDS and ACM; Translational Research Center for Traumatic Brain Injury and Stress Disorders (TRACTS) Veterans Affairs Rehabilitation Research and Development Traumatic Brain Injury Center of Excellence (B6796-C) to ACM; National Institute of Neurological Disorders and Stroke, National Institute of Biomedical Imaging and Bioengineering (U01NS086659–01) to VEA, TDS, and ACM; National Institute of Aging Boston University AD Center (P30AG13846; supplement 0572063345–5) to TDS and ACM; Department of Defense Peer Reviewed Alzheimer’s Research Program (DoD-PRARP #13267017) to ACM; Concussion Legacy Foundation to ACM, the Emory Alzheimer’s Disease Research Center (P50AG025688, P30AG066511), Accelerating Medicine Partnership AD grant U01AG046161, NINDS K08NS087121 to CMH and DoD-PRARP AZ150143 to CMH. This work was also supported by unrestricted gifts from the Andlinger Foundation and WWE. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
• Keywords: Neurosciences; TAU; Proteomics; TAUOPATHIES; Tandem mass tagged (TMT); PATHOLOGY; Immunoglobulin; Frontotemporal dementia (FTD); ALZHEIMERS-DISEASE; Neurosciences & Neurology; Chronic traumatic encephalopathy (CTE); INJURY; DIAGNOSIS; Astrocyte; NEUROPATHOLOGY; Life Sciences & Biomedicine; Weighted gene co-expression network analysis (WGCNA); TRANSCRIPTOME; Science & Technology; SPECTRUM
• Research Categories: Health Sciences, Pathology; Chemistry, Biochemistry

Abstract

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.