Polyamination with spermidine enhances pathogenic tau conformations while reducing filamentous aggregate formation in vitro.

Tau is subject to a broad range of post-translational modifications (PTMs) that regulate its biological activity in health and disease, including microtubule (MT) dynamics, aggregation, and adoption of pathogenic conformations. The most studied PTMs of tau are phosphorylation and acetylation; however, the salience of other PTMs is not fully explored. Tissue transglutaminase (TG) is an enzyme whose activity is elevated in Alzheimer's disease (AD). TG action on tau may lead to intramolecular and intermolecular cross-linking along with the incorporation of cationic polyamines (e.g., spermidine [SPD]) onto glutamine residues (Q). Even though SPD levels are significantly elevated in AD, the effects of SPD polyamination on tau biology have yet to be examined. In this work, we describe a method to produce recombinant SPD-modified tau where SPD modifications are mainly localized to Q residues within the N-terminus. MT binding and polymerization assays showed that SPD modification does not significantly alter tau's binding to MTs but increases MT polymerization kinetics. In addition, biochemical and biophysical assays showed that SPD polyamination of tau markedly reduces tau polymerization into filamentous and β-sheet-containing aggregates. On the other hand, SPD modification promotes the formation of pathogenic conformations (e.g., oligomerization and misfolding) by tau with or without inducing tau polymerization. Taken together, these data suggest that SPD polyamination of tau enhances its ability to polymerize MTs and favors the adoption of pathogenic tau conformations but not filamentous aggregates in vitro.