Structurally Distinct Polymorphs of Tau Aggregates Revealed by Nanoscale Infrared Spectroscopy.

Aggregation of the tau protein plays a central role in several neurodegenerative diseases collectively known as tauopathies, including Alzheimer's and Parkinson's disease. Tau misfolds into fibrillar β sheet structures that constitute the paired helical filaments found in neurofibrillary tangles. It is known that there can be significant structural heterogeneities in tau aggregates associated with different diseases. However, while structures of mature fibrils have been studied, the structural distributions in early-stage tau aggregates is not well-understood. In the present study, we use atomic force microscopy-IR to investigate nanoscale spectra of individual tau fibrils at different stages of aggregation and demonstrate the presence of multiple fibrillar polymorphs that exhibit different secondary structures. We further show that mature fibrils contain significant amounts of antiparallel β sheets. Our results are the very first application of nanoscale infrared spectroscopy to tau aggregates and underscore the promise of spatially resolved infrared spectroscopy for investigating protein aggregation.