cn9b00458_si_001.pdf (1.88 MB)
Toward the Mode of Action of the Clinical Stage All‑d‑Enantiomeric Peptide RD2 on Aβ42 Aggregation
journal contribution
posted on 2019-11-21, 21:47 authored by Tao Zhang, Ian Gering, Janine Kutzsche, Luitgard Nagel-Steger, Dieter WillboldThe 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.