Tau Repeats Disassemble Amyloid-β Fibrils In Vitro by Interacting with KLVFFA and GGVVIA Domains

Abstract

The interplay between amyloid beta (A beta) and tau protein is acknowledged as a crucial factor in the progression of Alzheimer's disease (AD), yet the precise molecular mechanisms underlying their interaction remain elusive. In this study, we explore how the key regions within tau, specifically the repeat domains, modulate A beta aggregation. Through microscale thermophoresis and peptide mapping assays, we identified that tau repeats containing the amyloid motifs VQIINK and VQIVYK directly interact with A beta(1-42) and A beta(1-40), targeting the hydrophobic regions of A beta. Tau repeats were found to inhibit A beta fibril formation and promote the dissociation of preformed fibrils in vitro. Notably, while disassembling A beta(1-42) fibrils, tau repeats concurrently stabilized oligomeric forms. These findings provide valuable insights into the complex mechanisms by which tau influences the A beta pathology, with potential implications for AD progression.