Characterization of the Early Stages of Tau Aggregation in the Presence of Polyphosphates

Abstract

Tau is a microtubule associated protein implicated in the pathology of Alzheimer's disease and other neurodegenerative disorders through its aggregation and deposition as neurofibrillary tangles. However, the triggers of tau aggregation are not well characterized or understood. Tau is both an intrinsically disordered protein and it aggregates very slowly in vitro, making it challenging to study the mechanism of aggregation. Using single molecule fluorescence techniques we investigated the early stages of tau aggregation in the presence of the physiologically relevant aggregation inducer, polyphosphate (polyP). We find evidence that polyP accelerates tau aggregation through two different mechanisms: (1) conformational changes of monomer tau; and (2) intermolecular cross-linking of multiple tau through multiple polyP binding sites. PolyP binds to both the proline rich and microtubule binding regions, but the proline rich region is required for changes of conformation. The magnitude of the conformational shift and the aggregation of tau are dependent on the chain length of the polyP polymer, with longer polyP polymers causing greater conformational change and more rapid aggregation. PolyP also competes with tubulin, tau's native binding partner, providing further insight into possible triggers for the early stages of tau aggregation.