Template-assisted propagation of Tau fi brils is essential for the spreading of Tau
pathology in Alzheimer's disease. In this process, small seeds of fi brils recruit
Tau monomers onto their ends. The physical properties of the fi brils play an important
role in their propagation. Here, we describe two different electron paramagnetic resonance
(EPR) techniques that have provided crucial insights into the structure of Tau fi
brils. Both techniques rely on the site-directed introduction of one or two spin labels
into the protein monomer. Continuous-wave (CW) EPR provides information on which amino
acid residues are contained in the fi bril core and how they are stacked along the
long fi bril axis. Double electron-electron resonance (DEER) determines distances
between two spin labels within a single protein and hence provides insights into their
spatial arrangement in the fi bril cross section. Because of the long distance range
accessible to DEER (similar to 2-5 nm) populations of distinct fi bril conformers
can be differentiated.
