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@ARTICLE{Nedaei:996128,
author = {Nedaei, Hadi and Rezaei-Ghaleh, Nasrollah and Giller, Karin
and Becker, Stefan and Karami, Leila and Moosavi-Movahedi,
Ali Akbar and Griesinger, Christian and Saboury, Ali Akbar},
title = {{T}he calcium-free form of atorvastatin inhibits
amyloid-β(1–42) aggregation in vitro},
journal = {The journal of biological chemistry},
volume = {298},
number = {3},
issn = {0021-9258},
address = {Bethesda, Md.},
publisher = {Soc.},
reportid = {FZJ-2023-01125},
pages = {101662 -},
year = {2022},
abstract = {Alzheimer's disease is characterized by the presence of
extraneuronal amyloid plaques composed of amyloid-beta (Aβ)
fibrillar aggregates in the brains of patients. In mouse
models, it has previously been shown that atorvastatin
(Ator), a cholesterol-lowering drug, has some reducing
effect on the production of cerebral Aβ. A meta-analysis on
humans showed moderate effects in the short term but no
improvement in the Alzheimer's Disease Assessment
Scale—Cognitive Subscale behavioral test. Here, we explore
a potential direct effect of Ator on Aβ42 aggregation.
Using NMR-based monomer consumption assays and CD
spectroscopy, we observed a promoting effect of Ator in its
original form (Ator-calcium) on Aβ42 aggregation, as
expected because of the presence of calcium ions. The effect
was reversed when applying a CaCO3-based calcium ion
scavenging method, which was validated by the aforementioned
methods as well as thioflavin-T fluorescence assays and
transmission electron microscopy. We found that the
aggregation was inhibited significantly when the
concentration of calcium-free Ator exceeded that of Aβ by
at least a factor of 2. The 1H–15N heteronuclear single
quantum correlation and saturation-transfer difference NMR
data suggest that calcium-free Ator exerts its effect
through interaction with the 16KLVF19 binding site on the
Aβ peptide via its aromatic rings as well as hydroxyl and
methyl groups. On the other hand, molecular dynamics
simulations confirmed that the increasing concentration of
Ator is necessary for the inhibition of the conformational
transition of Aβ from an α-helix-dominant to a
β-sheet-dominant structure.},
cin = {IBI-7},
ddc = {540},
cid = {I:(DE-Juel1)IBI-7-20200312},
pnm = {5241 - Molecular Information Processing in Cellular Systems
(POF4-524)},
pid = {G:(DE-HGF)POF4-5241},
typ = {PUB:(DE-HGF)16},
pubmed = {35104501},
UT = {WOS:000794865600002},
doi = {10.1016/j.jbc.2022.101662},
url = {https://juser.fz-juelich.de/record/996128},
}