ja405239v_si_001.pdf (2.03 MB)
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
journal contribution
posted on 2013-11-06, 00:00 authored by Xueli Zhang, Yanli Tian, Zeng Li, Xiaoyu Tian, Hongbin Sun, Hong Liu, Anna Moore, Chongzhao RanIn
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.
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Keywords
HHQKLVFFAmyloid Beta Speciesamyloid betainteraction mechanismCRANADcopper bindingβ peptideWestern blotAD therapyVivo Fluorescence Imagingvivo NIR imagingstereohindrance compatibilityH 13fluorescence imaging probes4 monthscurcumin scaffoldβ peptidesCurcumin Analoguesfluorescence property changesβ plaquesimidazole ringsH 14β species
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