Effect of cellular polyanion mimetics on tau peptide aggregation

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Tau protein aggregation, particularly of hexapeptide sequences (VQIVYK and VQIINK), is a critical factor in Alzheimer's disease (AD) pathogenesis.
• Cellular microenvironmental polyanions are implicated in tau aggregation and subsequent functional loss, but their specific roles require further elucidation.
• Previous research primarily examined heparin and heparan sulfate effects on full-length tau protein.

Purpose of the Study:

• To investigate the impact of glycosaminoglycans (GAGs) and cellular RNA on the aggregation of specific tau peptide fragments, VQIVYK and a mutant tau peptide (GKVQIIN_KLDL).
• To explore the influence of GAGs in both solution and surface-bound states, mimicking different cellular microenvironments.
• To assess the aggregation-inducing and toxic effects of cellular RNA on tau peptides within neuroblastoma cells.

Main Methods:

• Biochemical assays, electron microscopy, and spectroscopy were employed to characterize tau peptide aggregation in vitro.
• The study utilized various glycosaminoglycans (GAGs) including heparin, chondroitin sulfate, and dermatan sulfate.
• Aggregation and toxicity were assessed in neuroblastoma cells following exposure to tau peptides and cellular RNA.

Main Results:

• GAGs in solution significantly promoted tau peptide aggregation, with heparin, chondroitin sulfate, and dermatan sulfate showing the most pronounced effects.
• Surface-bound GAGs did not significantly enhance tau aggregation.
• Cellular RNA markedly increased tau peptide aggregation and induced toxicity in neuroblastoma cells.

Conclusions:

• Cellular polyanions, especially specific GAGs in solution and cellular RNA, are potent inducers of tau peptide aggregation.
• The physical state of GAGs (solution vs. surface) influences their effect on tau aggregation.
• These findings offer insights into tau aggregation mechanisms and suggest potential therapeutic targets involving modulation of cellular polyanions for Alzheimer's disease treatment.