Unraveling the mechanism of tau protein aggregation in presence of zinc ion: The earliest step of tau aggregation

Abstract

Recent studies have indicated that tau protein aggregation is closely related to Alzheimer's disease. Though the later stages of the aggregation process are extensively studied, it is still unknown how the aggregation occurs in the earliest stage. It is reported that the presence of low micromolar zinc ions can trigger the aggregation process even without the presence of any cofactors like heparin. The earlier studies have indicated that zinc binds to the tau protein in a tetrahedral geometry, binding to two cysteine and two histidine residues. Nevertheless, the mechanism is still unclear on how the aggregation occurs, especially the early events that lead to the aggregation. Here we have used surface-enhanced Raman spectroscopy to study the aggregation process under the presence of zinc ions. We observed a broadening of the C-S stretching band upon the addition of zinc ions, which indicates a direct involvement of the zinc-binding domain in the aggregation process. We attribute that zinc ion promotes the intermolecular bridging of tau monomers through cysteine and histidine binding, and that triggers the aggregation process. Our finding suggests a plausible mechanism of tau protein aggregation under an imbalance of zinc ions inside the pathological brain.

Keywords

• Tau protein
• Aggregation
• Raman spectroscopic analysis