Toxicity inhibitors protect lipid membranes from disruption by Aβ42

ACS Chemical Neuroscience
Ravit MalishevRaz Jelinek

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 tha...Continue Reading

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Citations

Jun 28, 2018·Chemical Communications : Chem Comm·Ravit MalishevRaz Jelinek
Oct 14, 2019·Journal of Pharmaceutical and Biomedical Analysis·Angela De SimoneVincenza Andrisano
Jul 10, 2021·The Journal of Chemical Physics·S R NateshE J Haddadian
Jun 13, 2019·Biochemistry·Albert W PilkingtonJustin Legleiter
Sep 21, 2017·Journal of the American Chemical Society·Tae Su ChoiHugh I Kim
Mar 23, 2018·Biochemistry·Ravit MalishevLiraz Chai
Dec 14, 2019·ACS Chemical Neuroscience·Albert W PilkingtonJustin Legleiter
Oct 14, 2021·Cellular and Molecular Life Sciences : CMLS·Ofek OrenNiv Papo
Nov 23, 2021·ACS Chemical Neuroscience·Shani Ben-ZichriRaz Jelinek

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