TY  - JOUR
AU  - Nedaei, Hadi
AU  - Rezaei-Ghaleh, Nasrollah
AU  - Giller, Karin
AU  - Becker, Stefan
AU  - Karami, Leila
AU  - Moosavi-Movahedi, Ali Akbar
AU  - Griesinger, Christian
AU  - Saboury, Ali Akbar
TI  - The calcium-free form of atorvastatin inhibits amyloid-β(1–42) aggregation in vitro
JO  - The journal of biological chemistry
VL  - 298
IS  - 3
SN  - 0021-9258
CY  - Bethesda, Md.
PB  - Soc.
M1  - FZJ-2023-01125
SP  - 101662 -
PY  - 2022
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - 35104501
UR  - <Go to ISI:>//WOS:000794865600002
DO  - DOI:10.1016/j.jbc.2022.101662
UR  - https://juser.fz-juelich.de/record/996128
ER  -