Concentration-Based Analysis of Metal-Induced Tau Fibrillar versus non-fibrillar Aggregation: Implications for Neurotoxicity in Alzheimer's Disease.

Abstract

Tau protein aggregation is the most significant factor in Alzheimer's disease (AD) pathogenesis, and the accumulation of metal ions in the brain is considered a key factor in the development of this disease. Tau protein exhibits two distinct aggregate structures: fibrillar and non-fibrillar aggregates. In this study, we conducted the first detailed study of the interactions of tau protein with three different concentrations of Zn²⁺, Cu²⁺, and Fe³⁺ions. Our findings demonstrate that low concentrations (0.01 mM) of these metal ions promote tau fibrillation, while higher concentrations (1 mM) induce non-fibrillar aggregates. We have investigated the structural changes of tau by using advanced techniques such as SDS-PAGE, DTNB, AFM, CD and fluorescence spectroscopy. At low concentrations, Zn²⁺ ions produced shorter fibrils, whereas Cu²⁺ and Fe³⁺ ions resulted in longer fibrils. CD showed increased β-sheet structures with a decrease in random coil content. Interestingly, Cu²⁺ ions caused a significant decrease in neuronal viability. Our data highlights a new approach that illuminates the different ways in which the metal ions distinctively cause tau fibrillar versus non-fibrillar aggregates, linked to neurotoxicity and neurodegeneration.