Curcumin and Homotaurine Suppress Amyloid-β_25–35 Aggregation in Synthetic Brain Membranes

Abstract

Amyloid-β (Aβ) peptides spontaneously aggregate into βand cross-β-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 Aβ 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 Aβ 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 Aβ aggregates and the corresponding βand cross-β-sheet signals. While a number of research projects focus on potential drug candidates that target Aβ 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.

Biflavones inhibit the fibrillation and cytotoxicity of the human islet amyloid polypeptide

“…An MTT assay was conducted to study the viability of INS-1 cells regulated by inhibitors. 66 15 mM caffeic acid shows a remarkable inhibitory effect on the formation of hIAPP fibrils, so it can be used as a negative control in the experiments. After incubating 15 mM hIAPP with the cells, the viability was 39.5 AE 1.0%, coincident with that reported previously.…”

Curcumin Reduces Amyloid Beta Oligomer Interactions with Anionic Membranes

“…This has been studied using Aβ 25–35, which is thought to be the predominant segment required for β-sheet formation and toxicity. Curcumin reduced the amount of β-sheet-rich structures formed on the membrane surface, measured by circular dichroism spectroscopy, thioflavin T fluorescence, and X-ray diffraction. , This reduction in Aβ 25–35 aggregation was attributed to curcumin’s thinning effect on the membrane, suggesting monomeric Aβ preferentially inserts into thicker and more ordered membranes . Another study measuring Aβ 1–42 aggregation using thioflavin T and immunoassays showed that curcumin-decorated liposomes reduced Aβ aggregation compared to pure liposomes .…”

CoVAMPnet: Comparative Markov State Analysis for Studying Effects of Drug Candidates on Disordered Biomolecules

“…Even at high concentrations, it is well tolerated in the human brain, where it is metabolized into 3-sulfopropanoic acid (SPA) (Figure A). TMP has been reported to prevent the formation of fibrillar forms of Aβ, reduce the Aβ-induced death rate of neuronal cell cultures, and lower the amyloid plaque deposition in the brain. − Clinical trials have shown its ability to slow down the cognitive decline in patients with homozygous expression of the apolipoprotein E gene APOE4 , similarly to FDA-approved aducanumab. , TMP can act not only on Aβ, but also on other pathways that contribute to cognitive impairment in AD and other neurologic disorders. , ALZ-801 is a valine-conjugated prodrug of TMP that is currently in phase 3 of clinical trials for early stage AD patients bearing the APOE4/4 genotype (NCT04770220). , Preliminary in vitro and in silico studies suggested that both TMP and SPA can lock the Aβ peptides in monomeric conformations that are less prone to oligomerization, thus inhibiting the first step in the pathological pathway of Aβ. − However, these studies do not provide sufficient insights to fully explain the mechanism of action of these molecules on Aβ. At the moment, it is still unclear whether TMP or its metabolite SPA can exert a stronger biological effect, and this was one of our motivations to carry out this study.…”