10.1021/acschemneuro.9b00458.s001
Tao Zhang
Tao
Zhang
Ian Gering
Ian
Gering
Janine Kutzsche
Janine
Kutzsche
Luitgard Nagel-Steger
Luitgard
Nagel-Steger
Dieter Willbold
Dieter
Willbold
Toward the
Mode of Action of the Clinical Stage All‑d‑Enantiomeric
Peptide RD2 on Aβ42 Aggregation
American Chemical Society
2019
surface plasmon resonance measurements
β42 monomers
AD mouse models
β42 monomer binding
compound RD 2
RD 2
β42. RD 2
2019-11-21 21:47:13
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Toward_the_Mode_of_Action_of_the_Clinical_Stage_All_d_Enantiomeric_Peptide_RD2_on_A_42_Aggregation/10710761
The 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.