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SELECTION AND CHARACTERIZATION OF A NOVEL FULL LENGTH TAU TARGETING D-AMINO ACID PEPTIDE AS A POTENTIAL THERAPEUTIC APPROACH FOR ALZHEIMER’S DISEASE
Abstract
Aims
One of the pathological hallmarks of Alzheimer’s disease (AD) is abnormally aggregated Tau protein. We aimed to develop novel D-amino acid peptides as Tau aggregation inhibitors, that were selected against full length Tau. It has already been demonstrated that D-amino acid peptides are protease stable and less immunogenic than L-amino acid peptides, what makes them suitable for possible in vivo applications. Binding of the D-peptides to Tau as a monomer or small oligomer could provide an early point of intervention in the pathological fibrillization cascade.
Methods
Using phage display against full-length Tau, we selected a novel Tau binding peptide, designated ISAD1. The D-peptides' ability in Tau binding and inhibition of Tau fibrilization was characterized using ELISA, ThT assays, dynamic light scattering, pelleting assays, in silico modeling and cell culture experiments.
Results
ISAD1 bound Tau in the PHF6 region and inhibited fibrillization of wild type Tau, diverse disease associated Tau mutants and a pro-aggregant repeat domain Tau mutant. In silico modelling of the D-amino acid peptide - Tau interaction suggested a similar binding mode to that known for other PHF6 binding peptides. ISAD1 induced the formation of large high molecular weight Tau aggregates that lack proper Thioflavin positive β-sheet conformation. Cell culture experiments demonstrated that ISAD1 is taken up by N2a cells efficiently and prevents cytotoxicity of externally added Tau fibrils.
Conclusions
Based on our results, it appears that ISAD1 could emerge as a promising therapy for early intervention of AD, presumably by inhibiting toxic Tau oligomer formation and promoting off-pathway assembly of Tau.