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P4‐051: Structural insight into the mechanism of beta‐amyloid toxicity and its inhibition by small molecules
Author(s) -
Bitan Gal,
Sinha Sharmistha,
Lopes Dahabada,
Du Zhenming,
Maiti Panchanan,
Klärner FrankGerrit,
Schrader Thomas,
Wang Chunyu
Publication year - 2012
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2012.05.1753
Subject(s) - toxicity , chemistry , small molecule , cytotoxicity , biochemistry , amyloid (mycology) , neurotoxicity , in vitro , pharmacology , biology , inorganic chemistry , organic chemistry
Background: Amyloid b-protein (Ab) neurotoxicity is central in Alzheimer’s disease (AD) pathogenesis. The mechanisms by which Ab causes toxicity and the details of how small molecule modulators inhibit toxicity are open questions. Our recent discovery that Lys-specific molecular tweezers are effective inhibitors of Ab toxicity provides clues for answering these questions.Methods: The toxicity and self-assembly of Ab analogues containing Lysy’Ala substitutions was studied in vitro. Inhibition of Abinduced toxicity by the molecular tweezer CLR01, the sugar derivative scyllo-inositol, and the green-tea polyphenol EGCG was compared in cell culture. The interaction of CLR01 and EGCG with Ab was compared using 2D, heteronuclear, solution-state NMR. Results: Lys16 was found to be a major mediator of Ab toxicity, whereas Lys28 plays a key role in Ab assembly. CLR01 and EGCG are effective inhibitors of Ab oligomerization and toxicity, whereas scyllo-inositol is a substantially weaker inhibitor. CLR01 binds Ab already at the monomer state at defined positions, whereas EGCG binds Abmonomers weakly and non-specifically.Conclusions: The Lys residues in Ab are important for the peptide’s assembly and toxicity and therefore are attractive targets for development of small-molecule inhibitors of Ab-induced toxicity. Understanding the mechanism by which inhibitors and modulators work may facilitate future drug development.