Isabelle Aillaud, Germany
Coburg University of Applied Sciences and Arts Institute of BioanalysisAuthor Of 1 Presentation
WHICH OF THE TWO HEXAPEPTIDE MOTIFS WITHIN TAU, PHF6 OR PHF6*, IS THE MORE PROMISING TARGET FOR THE DEVELOPMENT OF TAU AGGREGATION INHIBITORS?
Abstract
Aims
Alzheimer’s disease (AD) is pathologically characterized by the accumulation of protein aggregates in the brain, i. e. so called amyloid plaques composed of the β-amyloid peptide (Aß), and neurofibrillary tangles composed of the microtubule-associated protein Tau. Inhibitors of pathological Tau aggregation are attractive for the development of new therapeutic compounds. Two hexapeptide motifs within Tau, designated PHF6* (275VQIINK280) and PHF6 (306VQIVYK311), are known to be essential for tau aggregation. Recently, the PHF6* segment has been described as the more potent driver of tau aggregation. This study focuses on the phage-display selection of D-enantiomeric peptides that bind to the aggregation prone sequence motifs within tau to inhibit pathological tau aggregation. We would like to find out which of the two hexapeptide motifs of Tau is the more promising target for therapy development.
Methods
Employing mirror-image phage display with a large peptide library, we have identified PHF6* fibril binding peptides consisting of D-enantiomeric amino acids. D-enantiomeric peptides are extremely protease stable and considerably less immunogenic than L-peptides. The most interesting peptide and its influence on Tau aggregation was investigated using various biochemical and biophysical methods, and compared to the performance of PHF6-binding peptides selected earlier by our and other groups.
Results
The most promising peptide and its retro-inverso form inhibited PHF6*, TauRDΔK280 and full-length Tau fibrilization in vitro. Furthermore, the peptides were able to penetrate cells.
Conclusions
From our preliminary data, it seems likely that PHF6 and PHF6* aggregation inhibitors are comparably effective in inhibiting the aggregation of full-length tau in vitro.