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

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Repetitive head injury (RHI) is linked to chronic traumatic encephalopathy (CTE), a neurodegenerative disease characterized by tau protein aggregation.
• The molecular mechanisms driving abnormal protein accumulation in CTE remain poorly understood.
• This study investigated the human brain proteome across CTE stages to elucidate disease pathogenesis.

Purpose of the Study:

• To identify and characterize protein changes in the brain at different stages of chronic traumatic encephalopathy (CTE).
• To compare the proteomic profile of CTE with other tauopathies like frontotemporal lobar degeneration with MAPT mutations (FTLD-MAPT) and Alzheimer's disease (AD).
• To uncover unique molecular pathways and potential therapeutic targets in CTE pathogenesis.

Main Methods:

• Utilized isobaric tandem mass tagged labeling and mass spectrometry (TMT-MS) to analyze post-mortem cortical tissues from control, CTE, and FTLD-MAPT cases.
• Applied weighted gene co-expression network analysis (WGCNA) to identify modules of correlated proteins associated with disease phenotypes.
• Compared proteomic findings with network analysis data from Alzheimer's disease (AD) brain samples.

Main Results:

• Over 6000 unique proteins were identified across CTE stages, categorized into 28 WGCNA modules.
• CTE brains showed reduced neuronal proteins (neurodegeneration) and increased inflammation and glial cell markers, similar to AD.
• Unique CTE modules exhibited enrichment of immunoglobulins (e.g., IGHM, IGLL5) and extracellular matrix (ECM) proteins, with progressive changes observed across CTE stages.
• Astrocyte protein abundance levels in CTE were intermediate between controls and FTLD-MAPT, suggesting distinct glial responses.

Conclusions:

• Thousands of protein alterations were identified in CTE postmortem brains, highlighting similarities in neurodegeneration and inflammation pathways with AD.
• Distinct CTE-specific progressive changes, including immunoglobulin and ECM protein enrichment even in early stages, were discovered.
• Early and sustained alterations in astrocyte modules were noted in CTE.
• The significant overlap with FTLD-MAPT confirmed CTE as part of the tauopathy spectrum and revealed stage-specific molecular phenotypes crucial for understanding pathogenesis.