Toxicity Inhibitors Protect Lipid Membranes from Disruption by Aβ42

Although the precise molecular factors linking amyloid beta-protein (A beta) to Alzheimer's disease (AD) have not been deciphered, interaction of A beta with cellular membranes has an important role in the disease. However, most therapeutic strategies targeting A beta have focused on interfering with A beta self-assembly rather than with its membrane interactions. Here, we studied the impact of three toxicity inhibitors on membrane interactions of A beta 42, the longer form of A beta, which is associated most strongly with AD. The inhibitors included the four-residue C-terminal fragment A beta(39-42), the polyphenol (-)-epigallocatechin-3-gallate (EGCG), and the lysine-specific molecular tweezer, CLROI, all of which previously were shown to disrupt different steps in A beta 42 self-assembly. Biophysical experiments revealed that incubation of A beta 42 with each of the three modulators affected membrane interactions in a distinct manner. Interestingly, EGCG and CLROI were found to have significant interaction with membranes themselves. However, membrane bilayer disruption was reduced when the compounds were preincubated with A beta 42, 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 A beta 42 assembly differently, membrane interactions were significantly inhibited upon incubation of each compound with A beta 42, suggesting that preventing the interaction of A beta 42 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 A beta 42 toxicity inhibitors and should be taken into account in potential therapeutic strategies, in addition to disruption or remodeling of amyloid assembly.