Tau Derived Hexapeptide AcPHF6 Promotes Beta-Amyloid (Aβ) Fibrillogenesis

We studied the interactions of a tau derived hexapeptide AcPHF6 with beta-amyloid peptides A beta 40 and A beta 42 which reveals its unusual ability to promote A beta fibrillogenesis. The results demonstrate that the N-acetylated and C-amidated AcPHF6 hexapeptide can cause significant acceleration in A beta 40 and A beta 42 fibril growth. Aggregation kinetic studies at pH 7.4 show that at 25 mu M, AcPHF6 hexapeptide was able to cause similar to 2.3-fold increase in A beta 40 fibrillogenesis dramatically changing the aggregation kinetics. In addition, AcPHF6 peptide was able to reduce cellular toxicity mediated by A beta 40 and A beta 42 in hippocampal neuronal cell line (HT22). Computational studies suggest that the AcPHF6 peptide can act as an anchor and provides a hydrophobic surface for A beta monomer to bind and undergo rapid fibrillogenesis to form less toxic fibrils and alter the aggregation kinetics. At the molecular level we propose a dock-and-pack mechanism where the AcPHF6 hexapeptide aggregates can stabilize the beta-hairpin and promote rapid A beta self-assembly and growth to form less toxic oligomers or fibrils. Our results have direct implications in designing novel peptide/peptidomimetics as novel pharmacological tools to study protein aggregation and potentially prevent A beta-mediated toxicity in Alzheimer's disease.