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@ARTICLE{Zhang:872743,
author = {Zhang, Tao and Gering, Ian and Kutzsche, Janine and
Nagel-Steger, Luitgard and Willbold, Dieter},
title = {{T}oward the {M}ode of {A}ction of the {C}linical {S}tage
{A}ll- d -{E}nantiomeric {P}eptide {RD}2 on {A}β42
{A}ggregation},
journal = {ACS chemical neuroscience},
volume = {10},
number = {12},
issn = {1948-7193},
address = {Washington, DC},
publisher = {ACS Publ.},
reportid = {FZJ-2020-00221},
pages = {4800 - 4809},
year = {2019},
abstract = {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.},
cin = {ICS-6},
ddc = {540},
cid = {I:(DE-Juel1)ICS-6-20110106},
pnm = {553 - Physical Basis of Diseases (POF3-553)},
pid = {G:(DE-HGF)POF3-553},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:31710458},
UT = {WOS:000503918400005},
doi = {10.1021/acschemneuro.9b00458},
url = {https://juser.fz-juelich.de/record/872743},
}