title: Toxicity inhibitors protect lipid membranes from disruption by Aβ42.
abstract: Although the precise molecular factors linking amyloid β-protein (Aβ) to Alzheimer's disease (AD) have not been deciphered, interaction of Aβ with cellular membranes has an important role in the disease. However, most therapeutic strategies targeting Aβ have focused on interfering with Aβ self-assembly rather than with its membrane interactions. Here, we studied the impact of three toxicity inhibitors on membrane interactions of Aβ42, the longer form of Aβ, which is associated most strongly with AD. The inhibitors included the four-residue C-terminal fragment Aβ(39-42), the polyphenol (-)-epigallocatechin-3-gallate (EGCG), and the lysine-specific molecular tweezer, CLR01, all of which previously were shown to disrupt different steps in Aβ42 self-assembly. Biophysical experiments revealed that incubation of Aβ42 with each of the three modulators affected membrane interactions in a distinct manner. Interestingly, EGCG and CLR01 were found to have significant interaction with membranes themselves. However, membrane bilayer disruption was reduced when the compounds were preincubated with Aβ42, suggesting that binding of the assembly modulators to the peptide attenuated their membrane interactions. Importantly, our study reveals that even though the three tested compounds affect Aβ42 assembly differently, membrane interactions were significantly inhibited upon incubation of each compound with Aβ42, suggesting that preventing the interaction of Aβ42 with the membrane contributes substantially to inhibition of its toxicity by each compound. The data suggest that interference with membrane interactions is an important factor for Aβ42 toxicity inhibitors and should be taken into account in potential therapeutic strategies, in addition to disruption or remodeling of amyloid assembly.
authors: Department of Chemistry, Ben Gurion University of the Negev , Beer Sheva 84105, Israel.
authors: Ravit
authors: R
authors: Malishev
authors: Department of Chemistry, Ben Gurion University of the Negev , Beer Sheva 84105, Israel.
authors: Sukhendu
authors: S
authors: Nandi
authors: Ilse Katz Institute for Nanotechnology, Ben Gurion University of the Negev , Beer Sheva 84105, Israel.
authors: Sofiya
authors: S
authors: Kolusheva
authors: Department of Chemistry, Ben Gurion University of the Negev , Beer Sheva 84105, Israel.
authors: Yael
authors: Y
authors: Levi-Kalisman
authors: Institute of Organic Chemistry, University of Duisburg-Essen , Essen 45117, Germany.
authors: Frank-Gerrit
authors: FG
authors: Klärner
authors: Institute of Organic Chemistry, University of Duisburg-Essen , Essen 45117, Germany.
authors: Thomas
authors: T
authors: Schrader
authors: Department of Neurology, David Geffen School of Medicine, Brain Research Institute, and Molecular Biology Institute, University of California at Los Angeles , Los Angeles, California 90095, United States.
authors: Gal
authors: G
authors: Bitan
authors: Department of Chemistry, Ben Gurion University of the Negev , Beer Sheva 84105, Israel.|Ilse Katz Institute for Nanotechnology, Ben Gurion University of the Negev , Beer Sheva 84105, Israel.
authors: Raz
authors: R
authors: Jelinek
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000737:chemistry / Q000494:pharmacology*; D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D020285:Cryoelectron Microscopy; D004134:Dimyristoylphosphatidylcholine / Q000737:chemistry; D031541:Fluorescence Resonance Energy Transfer; D007700:Kinetics; D008051:Lipid Bilayers / Q000737:chemistry*; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D010755:Organophosphates / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D010715:Phosphatidylglycerols / Q000737:chemistry; D055503:Protein Multimerization / Q000187:drug effects; D017433:Protein Structure, Secondary; D053835:Unilamellar Liposomes / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D001952:Bridged-Ring Compounds; C583031:CLR01 compound; D008051:Lipid Bilayers; D018696:Neuroprotective Agents; D010755:Organophosphates; D010446:Peptide Fragments; D010715:Phosphatidylglycerols; D053835:Unilamellar Liposomes; C570535:amyloid beta-peptide (39-42); C075222:amyloid beta-protein (1-42); D002392:Catechin; C002773:dimyristoylphosphatidylglycerol; C045651:epigallocatechin gallate; D004134:Dimyristoylphosphatidylcholine
keywords: Molecular tweezer; amyloid β-protein (Aβ); fibril inhibitors; membrane interactions; polyphenols