Selection and Characterization of Tau Binding ᴅ-Enantiomeric Peptides with Potential for Therapy of Alzheimer Disease

Language
en
Document Type
Article
Issue Date
2017-01-24
Issue Year
2016
Authors
Dammers, Christina
Yolcu, Deniz
Kukuk, Laura
Willbold, Dieter
Pickhardt, Marcus
Mandelkow, Eckhard
Horn, Anselm H. C.
Sticht, Heinrich
Malhis, Marwa Nidal
Will, Nadja
Editor
Abstract

A variety of neurodegenerative disorders, including Alzheimer disease (AD), are associated with neurofibrillary tangles composed of the tau protein, as well as toxic tau oligomers. Inhibitors of pathological tau aggregation, interrupting tau self-assembly, might be useful for the development of therapeutics. Employing mirror image phage display with a large peptide library (over 109 different peptides), we have identified tau fibril binding peptides consisting of d-enantiomeric amino acids. d-enantiomeric peptides are extremely protease stable and not or less immunogenic than l-peptides, and the suitability of d-peptides for in vivo applications have already been demonstrated. Phage display selections were performed using fibrils of the d-enantiomeric hexapeptide VQIVYK, representing residues 306 to 311 of the tau protein, as a target. VQIVYK has been demonstrated to be important for fibril formation of the full lengths protein and forms fibrils by itself. Here, we report on d-enantiomeric peptides, which bind to VQIVYK, tau isoforms like tau3RD (K19) as well as to full lengths tau fibrils, and modulate the aggregation of the respective tau form. The peptides are able to penetrate cells and might be interesting for therapeutic and diagnostic applications in AD research.

Journal Title
PLoS ONE
Volume
11
Issue
12
Citation
PLoS ONE 11.12 (2016). <http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167432>
Zugehörige ORCIDs