Differentiating Aβ40 and Aβ42 in amyloid plaques with a small molecule fluorescence probe.

Differentiating amyloid beta (Aβ) subspecies Aβ40 and Aβ42 has long been considered an impossible mission with small-molecule probes. In this report, based on recently published structures of Aβ fibrils, we designed iminocoumarin-thiazole (ICT) fluorescence probes to differentiate Aβ40 and Aβ42, among which Aβ42 has much higher neurotoxicity. We demonstrated that robustly responds to Aβ fibrils, evidenced by turn-on fluorescence intensity and red-shifting of emission peaks. Remarkably, showed different spectra towards Aβ40 and Aβ42 fibrils. results demonstrated that could be used to differentiate Aβ40/42 in solutions. Moreover, our data revealed that could be used to separate Aβ40/42 components in plaques of AD mouse brain slides. In addition, two-photon imaging suggested that was able to cross the BBB and label plaques . Interestingly, we observed that was specific toward plaques, but not cerebral amyloid angiopathy (CAA) on brain blood vessels. Given Aβ40 and Aβ42 species have significant differences of neurotoxicity, we believe that can be used as an important tool for basic studies and has the potential to provide a better diagnosis in the future.