Phosphorylation differentially regulates tau isoforms

Background Six major tau isoforms are alternatively spliced in an age‐dependent manner: 3R tau (3‐repeat domain) is expressed in development, while both 3R and 4R (4‐repeat domain) tau isoforms are expressed in adult brain. While FTDP‐17‐causing point mutations in tau show isoform‐dependent effects on aggregation and microtubule stabilization, there are not tau mutations linked to Alzheimer’s disease. Meanwhile, effects of phosphorylation on different tau isoforms remain largely unexplored. Method We use a combination of recombinant proteins, mouse aging studies and iPSC‐derived neurons to test for isoform‐dependent effects of tau phosphorylation on its function and dysfunction. Result Phosphorylation at certain sites selectively diminishes microtubule polymerization activity by the fetal tau isoform while a comparable adult isoform was largely unaffected. Conversely, phosphorylation at these same sites accelerated in vitro aggregation of an adult isoform compared to the fetal isoform. Conclusion Phosphorylation to tau has isoform‐dependent effects on its function and dysfunction, thus emphasizing the importance of distinguishing pathological and regulatory phospho‐tau species in future therapeutic efforts.