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

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.