Exploring the interplay between fibrillization and amorphous aggregation channels on the energy landscapes of tau repeat isoforms

Significance Proteins involved in neurodegenerative disease often aggregate, leading both to amorphous phase separation and to fibrillization. Tau protein involved in Alzheimer’s and Pick’s diseases is in this class. We show that the free-energy landscapes display two channels of tau aggregation: one which leads to more ordered amyloid fibrils and a nonfibrillar channel that leads to amorphous phases. The nonfibrillar oligomers have been suggested to be the pathogenic species. The distinct structural properties of the two channels show they must backtrack to interconvert between the two channels, suggesting a complex interplay between amorphous phase separation and the formation of ordered amyloid fibrils. This interplay is tuned by the way tau is phosphorylated and the specific isoforms at play.