IC-P2-142: Association of CSF total Tau and phospho-tau (181) with cerebral atrophy in mild cognitive impairment and Alzheimer's disease

Abstract

Alzheimer’s disease is a hyperphosphorylated form of the microtubulebinding protein tau. Hyperphosphorylation of tau, which occurs significantly within the proline-rich domain, is associated with structural and functional changes that are poorly understood. Understanding the relationship between hyperphosphorylation of tau and structural changes in tau is a central question in the mechanism of neurofibrillary tangle formation. Methods: Peptides and larger protein constructs derived from the proline-rich region of tau as well as other tau domains were synthesized with defined phosphrylation states. The non-phosphorylated and phosphorylated peptides and proteins were analyzed by NMR and circular dichroism in order to identify the specific local changes in the structure of tau that are induced by hyperphosphorylation. Results: Phosphorylation of serine and threonine residues throughout the proline-rich domain of tau induced structural changes from a disordered conformation to a type II polyproline helix. The largest phosphorylation-induced structural changes were observed in tau peptides derived from residues 174-183 or residues 229-238. Phosphorylation-induced changes to polyproline helix were also observed in tau peptides incorporating residues 211-219. Phosphorylation of tau peptides derived from tau residues 196-209 resulted in the disruption of a nascent -helix. In these peptides, phosphoserine and phosphothreonine residues exhibited ordered values of phi ( ) (3J N 3.1-6.2 Hz; mean 4.7 Hz) compared to non-phosphorylated serine and threonine, indicating specific conformational restriction upon phosphorylation. Phosphorylation within the proline-rich domain did not affect the cis-trans isomerization equilibrium of the peptides examined, suggesting that phosphorylation-associated cis-trans isomerism is due to long-range interactions. As the proline-rich domains are linker regions between hydrophobic and aggregation-prone domains of tau, these results suggest that global reorganization of tau may occur upon hyperphosphorylation of proline-rich domain in tau. These results provide insight into possible mechanisms of phosphorylation-dependent structural changes of tau in Alzheimer’s disease. Conclusions: Hyperphosphorylation within the proline-rich domain of tau can induce specific local structural changes from a disordered conformation to an ordered polyproline II helix conformation.