The Neuronal Tau Protein Blocks In Vitro Fibrillation of the Amyloid-β (Aβ) Peptide

Abstract

Two pathophysiological characteristics in brains of Alzheimer's disease are accumulation of aggregated Amyloid-β (Aβ) peptides and hyperphosphorylated tau proteins as extracellular senile plaques and intracellular neurofibrillary tangles (NFTs), respectively. Both types of deposits develop both independently and with combined pathological reciprocal effects. The interplay between native full-length tau protein (tau-441) and Aβ40 from a molecular point of view was addressed in this study by using a combination of techniques such as transmission electron microscopy (TEM), atomic force microscopy (AFM), NMR, circular dichroism and fluorescence spectroscopy. The interaction between native, non-phosphorylated tau-441 protein and different stages of the Aβ peptide aggregation in vitro were characterized. Tau-441 protein prevents Aβ40 fibrillation in a concentration-dependent manner (C. Wallin, Y. Hiruma, S. Wärmländer, I. Huvent, J. Jarvet, J. P. Abrahams, A. Gräslund, G. Lippens, J. Luo, JACS. 2018;140(126):8138-8146), monitored by Thioflavin T (ThT) kinetics. The attenuation of Aβ40 fibrillation was confirmed with TEM imaging, as an aggregated Aβ40 sample showed typical amyloid fibrils while more amorphous structures were found for samples incubated in the presence of tau-441. To test whether tau-441 influences the Aβ40 aggregation at an early stage with monomeric Aβ40, NMR and fluorescence polarization measurements were conducted. However, native tau-441 proteins did not display any specific monomeric interaction. In contrast, tau-441 displays a two magnitudes higher affinity towards fibrils compared to monomers, suggesting reduced fibril-induced secondary nucleation processes. The decrease in Aβ40 aggregation is most likely due to an interaction with low molecular weight oligomers and fibrils rather than soluble monomeric Aβ40 peptides. The interaction between Aβ40/tau-441 and resulting prevention of the Aβ40 fibrillation may indicate an important interplay between two misfolding proteins in Alzheimer's disease.