Journal
ACS CHEMICAL NEUROSCIENCE
Volume 12, Issue 8, Pages 1395-1405Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.1c00057
Keywords
Amyloid-beta aggregation; cross-beta-sheets; aggregation inhibitor; curcumin; homotaurine; Alzheimer's disease
Funding
- Natural Sciences and Engineering Research Council of Canada (NSERC) [RGPIN-2016-06450]
- Canada Foundation for Innovation (CFI)
- Ontario Ministry of Economic Development and Innovation
- Early Researcher Award of the Province of Ontario
- University Scholar of McMaster University
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The study found that curcumin and homotaurine can effectively reduce the aggregation of amyloid beta and have no observable impact on brain membranes. These drugs inhibit A beta aggregation by changing membrane properties and binding to A beta peptides. Membrane-lipid therapy may be an effective approach to inhibit peptide aggregation.
Amyloid-beta (A beta) peptides spontaneously aggregate into beta- and cross-beta-sheets in model brain membranes. These nanometer sized can fuse into larger micrometer sized clusters and become extracellular and serve as nuclei for further plaque and fibril growth. Curcumin and homotaurine represent two different types of A beta aggregation inhibitors. While homotaurine is a peptic antiaggregant that binds to amyloid peptides, curcumin is a nonpeptic molecule that can inhibit aggregation by changing membrane properties. By using optical and fluorescent microscopy, X-ray diffraction, and UV-vis spectroscopy, we study the effect of curcumin and homotaurine on A beta(25-35) aggregates in synthetic brain membranes. Both molecules partition spontaneously and uniformly in membranes and do not lead to observable membrane defects or disruption in our experiments. Both curcumin and homotaurine were found to significantly reduce the number of small, nanoscopic A beta aggregates and the corresponding beta- and cross-beta-sheet signals. While a number of research projects focus on potential drug candidates that target A beta peptides directly, membrane-lipid therapy explores membrane-mediated pathways to suppress peptide aggregation. Based on the results obtained, we conclude that membrane active drugs can be as efficient as peptide targeting drugs in inhibiting amyloid aggregation in vitro.
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