Tau forms oligomeric complexes on microtubules that are distinct from pathological oligomers in disease
Tau is a microtubule-associated protein, which facilitates the assembly and stability of neuronal microtubules in humans. 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 could be causing loss of tau function and toxicity. 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 pathological oligomers and could be pre-cursors of aggregation in pathology. Further, using SMLM and an unsupervised shape classification algorithm that we developed, we show that different tau phosphorylation states are associated with distinct higher order aggregate species in pathology. Our work elucidates tau's nanoscale composition under physiological and pathological conditions in vivo . ### Competing Interest Statement The authors have declared no competing interest.
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