Differentiating Aß40 and Aß42 in amyloid plaques with a small molecule fluorescence probe

Abstract

Differentiating amyloid beta (Aß) subspecies Aß40 and Aß42 has long been considered an impossible mission with small-molecule probes. In this report, based on recently published structures of Aß fibrils, we designed iminocoumarin-thiazole (ICT) fluorescence probes to differentiate Aß40 and Aß42, among which Aß42 has much higher neurotoxicity. We demonstrated thatICTAD-1robustly responds to Aß fibrils, evidenced by turn-on fluorescence intensity and red-shifting of emission peaks. Remarkably,ICTAD-1showed different spectra towards Aß40 and Aß42 fibrils.In vitroresults demonstrated thatICTAD-1could be used to differentiate Aß40/42 in solutions. Moreover, our data revealed thatICTAD-1could be used to separate Aß40/42 components in plaques of AD mouse brain slides. In addition, two-photon imaging suggested thatICTAD-1was able to cross the BBB and label plaquesin vivo. Interestingly, we observed thatICTAD-1was specific toward plaques, but not cerebral amyloid angiopathy (CAA) on brain blood vessels. Given Aß40 and Aß42 species have significant differences of neurotoxicity, we believe thatICTAD-1can be used as an important tool for basic studies and has the potential to provide a better diagnosis in the future.