English
 
Help Privacy Policy Disclaimer
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
  The calcium-free form of atorvastatin inhibits amyloid-β(1–42) aggregation in vitro

Nedaei, H., Rezaei-Ghaleh, N., Giller, K., Becker, S., Karami, L., Moosavi-Movahedi, A. A., et al. (2022). The calcium-free form of atorvastatin inhibits amyloid-β(1–42) aggregation in vitro. Journal of Biological Chemistry, 298(3): 101662. doi:10.1016/j.jbc.2022.101662.

Item is

Basic

show hide
Genre: Journal Article

Files

show Files
hide Files
:
3389579.pdf (Publisher version), 5MB
Name:
3389579.pdf
Description:
-
OA-Status:
Visibility:
Public
MIME-Type / Checksum:
application/pdf / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
-

Locators

show

Creators

show
hide
 Creators:
Nedaei, H., Author
Rezaei-Ghaleh, N.1, Author           
Giller, K.2, Author           
Becker, S.2, Author           
Karami, L., Author
Moosavi-Movahedi, A. A., Author
Griesinger, C.2, Author                 
Saboury, A. A., Author
Affiliations:
1Research Group of Protein Structure Determination using NMR, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society, ou_3350128              
2Department of NMR Based Structural Biology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society, ou_3350124              

Content

show
hide
Free keywords: beta peptide aggregation; amyloid-beta; alzheimers-disease; molecular-dynamics; mice involvement; statins; curcumin; binding; tau; strategies
 Abstract: Alzheimer's disease is characterized by the presence of extraneuronal amyloid plaques composed of amyloid-beta (A beta) 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 A beta. 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 A beta 42 aggregation. Using NMR-based monomer consumption assays and CD spectroscopy, we observed a promoting effect of Ator in its original form (Ator-calcium) on A beta 42 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 A beta by at least a factor of 2. The H-1-N-15 heteronuclear single quantum correlation and saturation-transfer difference NMR data suggest that calcium-free Ator exerts its effect through interaction with the (KLVF19)-K-16 binding site on the A beta 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 A beta from an alpha-helix-dominant to a beta-sheet-dominant structure.

Details

show
hide
Language(s): eng - English
 Dates: 2022-01-302022-03
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1016/j.jbc.2022.101662
 Degree: -

Event

show

Legal Case

show

Project information

show hide
Project name : -
Grant ID : RE 3655/2-1
Funding program : -
Funding organization : DFG
Project name : -
Grant ID : RE 3655/2-3
Funding program : -
Funding organization : DFG
Project name : -
Grant ID : -
Funding program : -
Funding organization : University of Tehran

Source 1

show
hide
Title: Journal of Biological Chemistry
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: -
Pages: 17 Volume / Issue: 298 (3) Sequence Number: 101662 Start / End Page: - Identifier: ISSN: 00219258