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 crosslinking of Aβ induced by copper. According to our previous results and the possible structural stereo-hindrance 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. In this report, according to our limited studies on the interaction mechanism between CRANAD-58 and Aβ, we also designed CRANAD-17 to attenuate the crosslinking 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 crosslinking 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.

Near-infrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer’s disease

“…CRANAD-2 could be considered a "smart" probe because it displayed a significant increase in fluorescence intensity, an emission blue shift, a lifetime change, and quantum yield improvement upon interacting with insoluble Aβ aggregates (47). However, we found that CRANAD-2 was not able to detect soluble Aβ species (46).…”

“…In our previous studies, we designed the imidazole-containing curcumin analog CRANAD-17, which could compete specifically with the H13, H14 of Aβ peptides and lead to a reduction of copper-induced Aβ cross-linking in vitro (46). We performed a preliminary in vivo therapeutic treatment of 4-mo-old APP/PS1 mice with CRANAD-17 for 6 mo.…”

“…In our previous studies, we designed and tested the NIRF probe CRANAD-58, a curcumin analog, for detecting both soluble and insoluble Aβs (46). However, its sensitivity for in vivo imaging of Aβs is lower than that of CRANAD-3 (the ratios of NIRF signal F (APP/PS1) / F (WT) are 2.29 vs. 1.71, 2.04 vs. 1.61, and 1.98 vs. 1.82 at 5-, 10-and 30-min, respectively, after the probe injection) (46). Therefore, we decided to use CRANAD-3 to monitor therapeutic effectiveness in the proof-of-concept studies in this report.…”

“…However, to the best of our knowledge, successful application of NIRF probes for monitoring therapeutic efficacy has not yet been reported. Our group recently has designed asymmetrical CRANAD-58 to match the hydrophobic (LVFF) and hydrophilic (HHQK) segments of Aβ peptides and demonstrated its applicability for the detection of both insoluble and soluble Aβs in vitro and in vivo (46). In this report, CRANAD-3 was designed to enhance the interaction with Aβs by replacing the phenyl rings of curcumin with pyridyls to introduce potential hydrogen bonds.…”

Chiral Metallohelical Complexes Enantioselectively Target Amyloid β for Treating Alzheimer’s Disease

“…The binding sites and different binding models between the chiral metal complexes and Aβ1-40 were further confirmed by NMR spectroscopy [49][50][51][52][53] . The 1 H NMR signals of the aromatic moieties (F19F20) 49,50 of Aβ1-40 underwent remarkably change upon addition of complex 2, revealing their interactions associated with these units (Figure 4A and 4D).…”