Tau forms oligomeric complexes on microtubules that are distinct from pathological oligomers in disease

Tau is a microtubule-associated protein, which promotes neuronal microtubule assembly and stability. Accumulation of tau into insoluble aggregates known as neurofibrillary tangles (NFTs) is a pathological hallmark of several neurodegenerative diseases. The current hypothesis is that small, soluble oligomeric tau species preceding NFT formation cause toxicity. However, thus far visualizing the spatial distribution of tau monomers and oligomers inside cells under physiological or pathological conditions has not been possible. Here, using single molecule localization microscopy (SMLM), we show that, in vivo, tau forms small oligomers on microtubules under physiological conditions. These physiological oligomers are distinct from those found in cells exhibiting tau aggregation and could be pre-cursors of aggregated tau in pathology. Further, using an unsupervised shape classification algorithm that we developed, we show that different tau phosphorylation states are associated with distinct tau aggregate species. Our work elucidates taus nanoscale composition under physiological and pathological conditions in vivo.