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| Item Type: | Article |
|---|---|
| Title: | The polyphenol EGCG directly targets intracellular amyloid-β aggregates and promotes their lysosomal degradation |
| Creators Name: | Secker, C. and Motzny, A.Y. and Kostova, S. and Buntru, A. and Helmecke, L. and Reus, L. and Steinfort, R. and Brusendorf, L. and Boddrich, A. and Neuendorf, N. and Diez, L. and Schmieder, P. and Schulz, A. and Czekelius, C. and Wanker, E.E. |
| Abstract: | The accumulation of amyloidogenic protein aggregates in neurons is a pathogenic hallmark of a large number of neurodegenerative diseases including Alzheimer's disease (AD). Small molecules targeting such structures and promoting their degradation may have therapeutic potential for the treatment of AD. Here, we searched for natural chemical compounds that decrease the abundance of stable, proteotoxic β-sheet-rich amyloid-β (Aβ) aggregates in cells. We found that the polyphenol (-)-epigallocatechin gallate (EGCG) functions as a potent chemical aggregate degrader (CAD) in SH-EP cells. We further demonstrate that a novel, fluorescently labeled EGCG derivative (EGC-dihydroxybenzoate (DHB)-Rhodamine) also shows cellular activity. It directly targets intracellular Aβ42 aggregates and competes with EGCG for Aβ42 aggregate binding in vitro. Mechanistic investigations indicated a lysosomal accumulation of Aβ42 aggregates in SH-EP cells and showed that lysosomal cathepsin activity is critical for efficient EGCG-mediated aggregate clearance. In fact, EGCG treatment leads to an increased abundance of active cathepsin B isoforms and increased enzymatic activity in our SH-EP cell model. Our findings suggest that intracellular Aβ42 aggregates are cleared through the endo-lysosomal system. We show that EGCG directly targets intracellular Aβ42 aggregates and facilitates their lysosomal degradation. Small molecules, which bind to protein aggregates and increase their lysosomal degradation could have therapeutic potential for the treatment of amyloid diseases. |
| Keywords: | Alzheimer’s Disease, Amyloid-ß, EGCG, Lysosome, Cathepsin, EGCG Derivatives |
| Source: | Journal of Neurochemistry |
| ISSN: | 0022-3042 |
| Publisher: | Wiley |
| Volume: | 166 |
| Number: | 2 |
| Page Range: | 294-317 |
| Date: | 18 July 2023 |
| Official Publication: | https://doi.org/10.1111/jnc.15842 |
| PubMed: | View item in PubMed |
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