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@ARTICLE{Rsener:851774,
author = {Rösener, Nadine and Gremer, Lothar and Reinartz, Elke and
König, Anna and Brener, Oleksandr and Heise, Henrike and
Hoyer, Wolfgang and Neudecker, Philipp and Willbold, Dieter},
title = {{A} {D}-enantiomeric peptide interferes with
hetero-association of amyloid-β oligomers and prion
protein},
journal = {The journal of biological chemistry},
volume = {293},
issn = {1083-351X},
address = {Bethesda, Md.},
publisher = {Soc.},
reportid = {FZJ-2018-05289},
pages = {jbc.RA118.003116 -},
year = {2018},
abstract = {Alzheimer’s disease (AD) is a progressive
neurodegenerative disorder that affects millions of people
worldwide. One AD hallmark is the aggregation of amyloid-β
(Aβ) into soluble oligomers and insoluble fibrils. Several
studies have reported that oligomers rather than fibrils are
the most toxic species in AD progression. Aβ oligomers bind
with high affinity to membrane-associated prion protein
(PrP), leading to toxic signaling across the cell membrane,
which makes the Aβ–PrP interaction an attractive
therapeutic target. Here, probing this interaction in more
detail, we found that both full-length, soluble human (hu)
PrP(23–230) and huPrP(23–144), lacking the globular
C-terminal domain, bind to Aβ oligomers to form large
complexes above the megadalton size range. Following
purification by sucrose density–gradient
ultracentrifugation, the Aβ and huPrP contents in these
hetero-assemblies were quantified by reversed-phase HPLC.
The Aβ:PrP molar ratio in these assemblies exhibited some
limited variation depending on the molar ratio of the
initial mixture. Specifically, a molar ratio of about four
Aβ to one huPrP in the presence of an excess of
huPrP(23–230) or huPrP(23–144) suggested that four Aβ
units are required to form one huPrP-binding site. Of note,
an Aβ-binding all-D-enantiomeric peptide, RD2D3, competed
with huPrP for Aβ oligomers and interfered with Aβ–PrP
hetero-assembly in a concentration-dependent manner. Our
results highlight the importance of multivalent epitopes on
Aβ oligomers for Aβ–PrP interactions and have yielded an
all-D-peptide-based, therapeutically promising agent that
competes with PrP for these interactions.},
cin = {ICS-6},
ddc = {570},
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:30131337},
UT = {WOS:000447256000001},
doi = {10.1074/jbc.RA118.003116},
url = {https://juser.fz-juelich.de/record/851774},
}