Capping of aβ42 oligomers by small molecule inhibitors.

Biochemistry (2014-11-26)
Ziao Fu, Darryl Aucoin, Mahiuddin Ahmed, Martine Ziliox, William E Van Nostrand, Steven O Smith
ABSTRACT

Aβ42 peptides associate into soluble oligomers and protofibrils in the process of forming the amyloid fibrils associated with Alzheimer's disease. The oligomers have been reported to be more toxic to neurons than fibrils, and have been targeted by a wide range of small molecule and peptide inhibitors. With single touch atomic force microscopy (AFM), we show that monomeric Aβ42 forms two distinct types of oligomers, low molecular weight (MW) oligomers with heights of 1-2 nm and high MW oligomers with heights of 3-5 nm. In both cases, the oligomers are disc-shaped with diameters of ~10-15 nm. The similar diameters suggest that the low MW species stack to form the high MW oligomers. The ability of Aβ42 inhibitors to interact with these oligomers is probed using atomic force microscopy and NMR spectroscopy. We show that curcumin and resveratrol bind to the N-terminus (residues 5-20) of Aβ42 monomers and cap the height of the oligomers that are formed at 1-2 nm. A second class of inhibitors, which includes sulindac sulfide and indomethacin, exhibit very weak interactions across the Aβ42 sequence and do not block the formation of the high MW oligomers. The correlation between N-terminal interactions and capping of the height of the Aβ oligomers provides insights into the mechanism of inhibition and the pathway of Aβ aggregation.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Curcumin, from Curcuma longa (Turmeric), powder
Sigma-Aldrich
Indomethacin, 98.5-100.5% (in accordance with EP)
Sigma-Aldrich
Curcumin, ≥94% (curcuminoid content), ≥80% (Curcumin)
Supelco
Curcumin, analytical standard
Supelco
Indomethacin, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
Curcumin, matrix substance for MALDI-MS, ≥99.5% (HPLC)
USP
Curcumin, United States Pharmacopeia (USP) Reference Standard
Sigma-Aldrich
Indomethacin, meets USP testing specifications
Sigma-Aldrich
Sulindac, ≥98.0%
Curcumin, primary reference standard
USP
Indomethacin, United States Pharmacopeia (USP) Reference Standard
Indomethacin, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Sulindac sulfide, ≥98% (HPLC), solid
Sigma-Aldrich
Sulindac, meets USP testing specifications
Sulindac, European Pharmacopoeia (EP) Reference Standard