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000872743 1001_ $$0P:(DE-Juel1)174389$$aZhang, Tao$$b0
000872743 245__ $$aToward the Mode of Action of the Clinical Stage All- d -Enantiomeric Peptide RD2 on Aβ42 Aggregation
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000872743 520__ $$aThe aggregation of amyloid-β (Aβ) into oligomers and fibrillary structures is critical for the pathogenesis of Alzheimer’s disease (AD). Recently, research effort has been focused on developing novel agents that can preferentially suppress Aβ oligomer mediated toxicities, for example, by directly targeting these toxic assemblies. The compound RD2 has been developed and optimized for Aβ42 monomer binding and stabilization of the monomer in its native intrinsically disordered conformation. It has been demonstrated to improve and even reverse the cognitive and behavioral deficits in AD mouse models, while the detailed mechanism of action is not fully clarified. Here we focused on exploring the interaction between RD2 and Aβ42 monomers and its consequences for the fibrillation of Aβ42. RD2 binds to Aβ42 monomers with nanomolar affinities, according to microscale thermophoresis and surface plasmon resonance measurements. Complexes between RD2 and Aβ42 monomers are formed at 1:1 and other stoichiometries, as revealed by analytical ultracentrifugation. At substoichiometric levels, RD2 slows down the secondary structure conversion of Aβ42 and significantly delays the fibril formation. Our research provides experimental evidence in supporting that RD2 eliminates toxic Aβ assemblies by stabilizing Aβ monomers in their native intrinsically disordered conformation. The study further supports the promising application of RD2 in counteracting Aβ aggregation related pathologies.
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000872743 7001_ $$0P:(DE-Juel1)171922$$aGering, Ian$$b1$$ufzj
000872743 7001_ $$0P:(DE-Juel1)159137$$aKutzsche, Janine$$b2$$ufzj
000872743 7001_ $$0P:(DE-Juel1)162443$$aNagel-Steger, Luitgard$$b3
000872743 7001_ $$0P:(DE-Juel1)132029$$aWillbold, Dieter$$b4$$eCorresponding author
000872743 773__ $$0PERI:(DE-600)2528493-9$$a10.1021/acschemneuro.9b00458$$gVol. 10, no. 12, p. 4800 - 4809$$n12$$p4800 - 4809$$tACS chemical neuroscience$$v10$$x1948-7193$$y2019
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