Background:Amyloidosis in Alzheimer’s disease (AD) starts with gradual aggregation of amyloid b (A beta) species into neurotoxic soluble dimers and oligomers, and insoluble fibrils and plaques. The aggregation process could be divided into two categories: reversible aggregation due to physical hydrophobic stacking, and irreversible aggregation due to covalent crosslinking. Many compounds have been shown to attenuate the aggregation process or to accelerate the aggregation into fibrils. However, few compounds have been able to inhibit covalent crosslinking of A beta.Methods: Fluorescent spectra and H NMRwere used to demonstrate the specificity of curcumin analogues towards specific region of Abeta. SDS-Page gel and western blots were used to evaluate the anti-crosslinking effects of the designed compounds. Results: Both fluorescence data and 1H NMR spectra indicated that one of the derivatives, CRANAD-3, could specifically interact with the core fragment of A b. In addition, our data suggested that CRANAD-3 certainly interactedwith H13 (histidine13), whose imidazolemoiety is an essential binding site for copper, which plays a critical role in covalent crosslinking of A b, and has been considered as an important triggering factor for AD. Furthermore, we designed and synthesized curcumin derivative CRANAD-17, in which imidazole rings were incorporated to compete with Histidine13 of A b for copper binding. SDS-PAGE and western blot results showed that CRANAD-17 was capable of inhibiting A b 42 crosslinking induced by copper. Conclusions: Our results indicate the possibility of using this compound for AD therapy. Since CRANAD-17 is also a fluorescent probe and could be easily adapted into a PET probe, it could potentially be used as a theranostic probe.