Effect of cellular polyanion mimetics on tau peptide aggregation

Abstract

Tau protein aggregation is believed to be one of the key drivers of Alzheimer's disease. The two hexapeptide amino acid sequences ³⁰⁶ VQIVYK³¹¹ and ²⁷⁵ VQIINK²⁸⁰ of the tau protein are responsible for aggregation, and subsequent functional loss leading to Alzheimer's progression. Hence, it is important to understand the factors that promote the self-aggregation of this tau peptide fragments. Cellular microenvironmental polyanions are known to play a major role in tau protein aggregation and loss of function. Previous studies mainly focused on the effect of heparin and heparan sulfate solution on the full tau protein aggregation. Here, we study the effect of cellular polyanion mimetics, glycosaminoglycans (GAGs) in solution and on surface to mimic intracellular and extracellular conditions, and cellular RNA on the aggregation of tau hexapeptide ³⁰⁶ VQIVYK³¹¹ , and mutant tau peptide ²⁷³ GKVQIIN_KLDL²⁸⁴ found frequently in taupathy. Characterization techniques used for the study include biochemical assays, electron microscopy, and spectroscopy techniques to investigate the aggregation vitro. Results show while all the GAGs in solution form play a role in tau peptides aggregation, heparin, chondroitin sulfate, and dermatan sulfate in particular significantly promote the tau peptides aggregation formation. On the other hand, surface-coated GAGs did not promote significant tau aggregation. As far as cellular RNA is concerned, results show significant increase in tau peptides aggregation and toxicity in neuroblastoma cells. The study on the tau peptides fragments aggregation in the presence of GAGs and cellular RNA could provide novel information on the tau aggregation mechanism and could open ways for developing cellular polyanions modulating therapeutics for treating Alzheimer's disease.

Keywords: Alzheimer's; RNA; aggregation; glycosaminoglycans; tau peptide.