Fig. 2. Tau oligomers are the most toxic species in disease.
A number of complex and inter-related factors, including alterations in post-translational modifications, truncation alternative splicing, mutations, co-factors, chaperones, oxidative stress and seeds (Aβ, α-synuclein) can lead to the formation of soluble, intermediate tau aggregates—tau oligomers. Tau oligomers may go on to form stable filaments, however, these highly dynamic structures appear to be far more toxic than tau fibrils and may lead to the spread of pathology and a number of downstream toxic effects. Thus, tau oligomers represent a bottleneck in the process of tau toxicity in disease and a likely important therapeutic target.