Design and synthesis of curcumin analogues for in vivo fluorescence imaging and inhibiting copper-induced cross-linking of amyloid beta species in Alzheimer's disease.

ABSTRACT: In this article, we first designed and synthesized curcumin-based near-infrared (NIR) fluorescence imaging probes for detecting both soluble and insoluble amyloid beta (A?) species and then an inhibitor that could attenuate cross-linking of A? induced by copper. According to our previous results and the possible structural stereohindrance compatibility of the A? peptide and the hydrophobic/hydrophilic property of the A?13-20 (HHQKLVFF) fragment, NIR imaging probe CRANAD-58 was designed and synthesized. As expected CRANAD-58 showed significant fluorescence property changes upon mixing with both soluble and insoluble A? species in vitro. In vivo NIR imaging revealed that CRANAD-58 was capable of differentiating transgenic and wild-type mice as young as 4 months old, the age that lacks apparently visible A? plaques and A? is likely in its soluble forms. According to our limited studies on the interaction mechanism between CRANAD-58 and A?, we also designed CRANAD-17 to attenuate the cross-linking of A?42 induced by copper. It is well-known that the coordination of copper with imidazoles on Histidine-13 and 14 (H13, H14) of A? peptides could initialize covalent cross-linking of A?. In CRANAD-17, a curcumin scaffold was used as an anchoring moiety to usher the designed compound to the vicinity of H13 and H14 of A?, and imidazole rings were incorporated to compete with H13/H14 for copper binding. The results of SDS-PAGE gel and Western blot indicated that CRANAD-17 was capable of inhibiting A?42 cross-linking induced by copper. This raises a potential for CRANAD-17 to be considered for AD therapy.

SUBMITTER: Zhang X 

PROVIDER: S-EPMC3927838 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature