title: 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 (Aβ) species and then an inhibitor that could attenuate cross-linking of Aβ induced by copper. According to our previous results and the possible structural stereohindrance compatibility of the Aβ peptide and the hydrophobic/hydrophilic property of the Aβ13-20 (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 Aβ 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 Aβ plaques and Aβ is likely in its soluble forms. According to our limited studies on the interaction mechanism between CRANAD-58 and Aβ, we also designed CRANAD-17 to attenuate the cross-linking of Aβ42 induced by copper. It is well-known that the coordination of copper with imidazoles on Histidine-13 and 14 (H13, H14) of Aβ peptides could initialize covalent cross-linking of Aβ. 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 Aβ, 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 Aβ42 cross-linking induced by copper. This raises a potential for CRANAD-17 to be considered for AD therapy.
authors.affiliation: Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School , Building 75, Charlestown, Massachusetts 02129, United States.
authors.forename: Xueli
authors.initials: X
authors.lastname: Zhang
authors.forename: Yanli
authors.initials: Y
authors.lastname: Tian
authors.forename: Zeng
authors.initials: Z
authors.lastname: Li
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Tian
authors.forename: Hongbin
authors.initials: H
authors.lastname: Sun
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Anna
authors.initials: A
authors.lastname: Moore
authors.forename: Chongzhao
authors.initials: C
authors.lastname: Ran
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000172:deficiency; D000818:Animals; D003300:Copper / Q000737:chemistry*; D003474:Curcumin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D005260:Female; D005456:Fluorescent Dyes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure; D013050:Spectrometry, Fluorescence
chemical_list: D016229:Amyloid beta-Peptides; D005456:Fluorescent Dyes; D003300:Copper; D003474:Curcumin