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.
Highlights
Alzheimer disease (AD) is the most common cause for dementia and a major global cause of disability and dependency, raising significant personal and economic issues
As it was hardly possible to synthesize D-enantiomeric full lengths tau protein for mirror image phage display, we realized the selections of a peptide library encoding more than 1 x 109 different random 12-amino acid sequences with fibrils of the Denantiomeric hexapeptide VQIVYK (D-PHF6) as the target
The fragment VQIVYK has been demonstrated to be indispensable for tau aggregation and forms itself fibrils, [12,13], we expected the resulting peptides to bind fibrils of the full lengths tau protein
Summary
Alzheimer disease (AD) is the most common cause for dementia and a major global cause of disability and dependency, raising significant personal and economic issues. Tau Binding D-Peptides of “Landeskonferenz der Frauenbeauftragten an bayrischen HAW”, and TAO
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