Thesis

Profiling Tau Hyperphosphorylation in Formalin-Fixed Paraffin Embedded Human Brain with Liquid Chromatography Tandem Mass Spectrometry

Tauopathies are a distinct family of neurodegenerative diseases with a wide range of cognitive, psychiatric and motor symptoms that are neuropathologically characterized by aberrant accumulation and hyperphosphorylation of tau, a microtubule-binding protein predominantly expressed in neurons. In this study, we developed a novel method for profiling tau phosphorylation in formalin-fixed paraffin-embedded human post-mortem brain tissue using liquid chromatography-tandem mass spectrometry. We used this approach to examine the nexopathic nature (i.e., the regional neuroanatomical vulnerability) of tauopathies and for the first time, extensively describe tau phosphorylation across brain regions in Alzheimer disease, primary agerelated tauopathy, progressive supranuclear palsy and chronic traumatic encephalopathy (n=3 per group). We validated tau photophosphorylation distribution heterogeneity and confirmed the association of epitopes with tau pathology. Our findings identified promising phospho-epitopes 68, 69; 231 & 237 preferentially expressed in regions developing tau pathology. These epitopes could potentially help us differentiate tauopathies and be useful as diagnostic tools.