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Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

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  • Published:
Neurotherapeutics

Abstract

Protein misfolding disorders, such as Alzheimer's disease and Parkinson's disease, have in common that a protein accumulates in an insoluble form in the affected tissue. The process of aggregation follows a mechanism of seeded polymerization. Although the toxic species is still not well defined, the process, rather than the end product, of fibril formation is likely the main culprit in amyloid toxicity. These findings suggest that therapeutic strategies directed against the protein misfolding cascade should focus on depleting aggregation intermediates rather than on large fibrillar aggregates. Recent studies involving natural compounds have suggested new intervention strategies. The polyphenol epi-gallocatechine-3-gallate (EGCG), the main polyphenol in Camilla sinensis, binds directly to a large number of proteins that are involved in protein misfolding diseases and inhibits their fibrillization. Instead, it promotes the formation of stable, spherical aggregates. These spherical aggregates are not cytotoxic, have a lower β-sheet content than fibrils, and do not catalyze fibril formation. Correspondingly, epi-gallocatechine-3-gallate remodels amyloid fibrils into aggregates with the same properties. Derivatives of Orcein, which is a phenoxazine dye that can be isolated from the lichen Roccella tinctoria, form a second promising class of natural compounds. They accelerate fibril formation of the Alzheimer’s disease-related amyloid-beta peptide. At the same time these compounds deplete oligomeric and protofibrillar forms of the peptide. These compounds may serve as proof-of-principle for the strategies of promoting and redirecting fibril formation. Both may emerge as two promising new therapeutic approaches to intervening into protein misfolding processes.

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Acknowledgments

The two main substances, EGCG and O4, that were discussed in this review were initially characterized by Dagmar Ehrnhöfer and Martin Herbst, respectively, in the laboratory of Professor Erich Wanker at the Max Delbrück Center for Molecular Medicine. I gratefully acknowledge his support, encouragement, and guidance in elucidating their underlying mechanisms of action. I would like to dedicate this work to the memory of Professor Werner Hunstein (1928–2012), who, in turning personal tragedy into research fervor, demonstrated that, through persistence and enthusiasm, the path from the bench to the bedside can be found.

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  1. Department of Biomedical Engineering, Washington University in St. Louis, One Brookings Drive, St. Louis, MO, 63130, USA

    Jan Bieschke

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Bieschke, J. Natural Compounds May Open New Routes to Treatment of Amyloid Diseases. Neurotherapeutics 10, 429–439 (2013). https://doi.org/10.1007/s13311-013-0192-7

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