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In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
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β-Bracelets: Macrocyclic Cross-β Epitope Mimics Based on a Tau Conformational Strain.
Benjamin H Rajewski1, Kamlesh M Makwana1, Isaac J Angera1
1Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States.
Journal of the American Chemical Society
|October 16, 2023
Summary
Researchers designed novel 'β-bracelets' that mimic toxic tau protein structures. These molecules inhibit tau aggregation and spread, offering a new strategy for Alzheimer's disease (AD) and tauopathy therapeutics.
Area of Science:
- Biochemistry
- Neuroscience
- Drug Discovery
Background:
- Misfolded tau protein aggregation into neurotoxic fibrils drives Alzheimer's disease (AD) and tauopathies.
- Disease-associated tau conformations involve hydrophobic interactions within β-strand modules.
Purpose of the Study:
- To design and synthesize novel peptide macrocycles mimicking tau's aggregation-prone cross-β structure.
- To evaluate these 'β-bracelets' as inhibitors of tau aggregation and seeding.
Main Methods:
- Diversity-oriented synthesis of β-arch peptide macrocycles incorporating the PHF6 hexapeptide.
- Characterization of macrocycle assembly into amyloid-like fibrils with in-register parallel β-sheet structure.
- Assessment of N-aminated β-bracelets as inhibitors of tau aggregation and cellular seeding.
Main Results:
- Developed 'β-bracelets', proteomimetics that self-assemble into amyloid-like fibrils.
- Demonstrated sequence- and macrocycle-dependent fibril formation.
- Showed that N-aminated β-bracelets effectively inhibit tau aggregation and block prion-like seeding.
Conclusions:
- Established 'β-bracelets' as a new class of cross-β epitope mimics.
- Validated the utility of β-bracelets in targeting amyloid propagation and seeding.
- Highlighted the therapeutic potential of β-bracelets for Alzheimer's disease and related tauopathies.
