Methods for Identification and Structural Characterization of Tau Polymorphs in Neurodegenerative Disease

Tauopathies are neurodegenerative diseases associated with the misfolding and aggregation of the tau protein in the brain, including Alzheimer's Disease (AD) and Chronic Traumatic Encephalopathy (CTE). Current medical technology is only able to definitively diagnose tauopathies post-mortem, which limits patient treatment options and reduces quality of life. Structural differences related to specific tauopathies ultimately result in unique disease progression and require unique treatments. In particular, CTE-related tauopathies are relatively understudied compared to AD. To improve diagnosis and treatment options for patients with CTE, it is essential to understand the role of tau in disease onset and progression. Experimental methods such as atomic force microscopy (AFM) and computational methods such as molecular dynamics simulations have been used to gain an understanding of pathological tau structure and mechanics. Spectroscopy and molecular probes have also been effective in revealing mechanisms of tau aggregation. State-of-the-art methods such as cryogenic electron microscopy and two-dimensional infrared spectroscopy (2DIR) are now being used to further explore tau at atomic resolution. In this review, we discuss the current state of both experimental and computational strategies in the assessment of tauopathies, specifically related to structural characterization. We highlight technological advances in relevant methods, such as AFM and 2DIR, that are pivotal to our understanding of structural amyloid formation and progression ante-mortem.