Objective: Stabilization of monomeric Tau protein by transient and high-affinity binding ligands is a novel and highly innovative anti-prionic treatment strategy for tauopathies.

Background: Tauopathies that are associated with movement disorders are for example progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). More and more in vitro and in vivo data suggest that toxic Tau assemblies behave prion-like. The presence of self-replicating and propagating etiologic agents in the brains of diseased patients has dramatic consequences for therapy development. Very importantly, the non-toxic and functional Tau monomer is chemically 100% identical to the building blocks in toxic Tau oligomers and fibrils, except maybe for phosphorylation. The only difference is their three-dimensional conformation. Tau monomers are intrinsically disordered proteins (IDPs) without defined rigid conformation. The same protein molecule in oligomer assemblies and fibrils does have a highly defined conformation that is even able to recruit monomers in order to grow and replicate. Identification of ligands that stabilize Tau monomers in their native IDP-like conformation is not a trivial or very intuitive, but possibly the most successful, strategy for the development of drugs that directly disassemble toxic oligomers into their native and functional monomer building blocks.

Method: We have identified all-D-peptides by mirror-image phage display against monomeric Tau that were further analyzed for their effect on Tau aggregation kinetics using Thioflavin-T (ThT) analysis, fluorescence microscopy and atomic force microscopy (AFM). The binding kinetics were analyzed using surface plasmon resonance (SPR). Tau oligomer elimination efficacy was measured by a Tau-QIAD assay.

Results: Especially one of the all-D-peptides (TFD-5) showed an exceptionally strong impact during the ThT-experiments. It inhibited heparin induced Tau fibril formation completely and changed the fibril morphology of pre-existing fibrils as seen in AFM. It strongly bound to the monomeric form of Tau as shown by SPR.

Conclusion: TFD-5 seems to be a promising lead candidate for a potential therapeutic approach, which aims at the destabilization and disassembly of toxic Tau assemblies into functional monomers. We will also report on the properties of the optimized leads.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/identification-and-characterization-of-anti-prionic-compounds-that-disassemble-tau-prions-as-a-novel-therapeutic-approach-for-tauopathies/