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

Abstract

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 <b>ICTAD-1</b> robustly responds to Aβ fibrils, evidenced by turn-on fluorescence intensity and red-shifting of emission peaks. Remarkably, <b>ICTAD-1</b> showed different spectra towards Aβ40 and Aβ42 fibrils. <i>In vitro</i> results demonstrated that <b>ICTAD-1</b> could be used to differentiate Aβ40/42 in solutions. Moreover, our data revealed that <b>ICTAD-1</b> could be used to separate Aβ40/42 components in plaques of AD mouse brain slides. In addition, two-photon imaging suggested that <b>ICTAD-1</b> was able to cross the BBB and label plaques <i>in vivo</i>. Interestingly, we observed that <b>ICTAD-1</b> 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 <b>ICTAD-1</b> can be used as an important tool for basic studies and has the potential to provide a better diagnosis in the future.