Differentiating Aβ40 and Aβ42 with a small‐molecule fluorescence probe

Abstract

AbstractBackgroundAmyloid beta (Aβ) plaque, one of the characteristic biomarkers for Alzheimer’s disease (AD), has been discovered more than 100 years in the postmortem brains of AD patients. However, the role of Aβ plaques in the pathology of AD has still been heavily debated, because the correlation between plaque burdens (numbers and areas) and the severity of AD is poor [2]. In the plaques, Aβ40 and Aβ42 peptides are major constituents. Nonetheless, unlike the role of plaque, there is nearly no argument that Aβ42 has much higher neurotoxicity than Aβ40 does. Conceivably, differentiating Aβ40 and Aβ42 can considerably clarify the role of plaque in AD pathology. Unfortunately, small‐molecule probes with such capacity are scarce. Due to the small difference of amino acid sequence of the peptides, discovering small‐molecule probes capable of differentiating Aβ40 and Aβ42 has been considered as an impossible mission.MethodBased on recently published structures of Aβ fibrils, we designed iminocoumarin‐thiazole (ICT) fluorescence probes to differentiate Aβ40 and Aβ42, among which Aβ42 has been considered to be much higher neurotoxic.ResultWe demonstrated that ICTAD‐1 robustly respond to Aβ fibrils, evidenced by turn‐on fluorescence intensity and red‐shifting of emission peaks. Remarkably, ICTAD‐1 showed different spectra towards Aβ40 and Aβ42 fibrils. In vitro results demonstrated that ICTAD‐1 could be used to differentiate Aβ40/42 in solutions. Moreover, our data revealed that ICTAD‐1 could be used to separate Aβ40/42 components in plaques of AD mouse brain slides. In addition, two‐photon imaging suggested that ICTAD‐1 was able to cross BBB and label plaques in vivo. Interestingly, we observed that ICTAD‐1 was specific toward plaques, but not cerebral amyloid angiopathy (CAA) on brain blood vessels.ConclusionIn summary, we demonstrated that ICTAD‐1 is the first probe of its kind for differentiating Aβ40/42. ICTAD‐1 has the potential to dissect the toxicity contributions of Aβ40 and Aβ42, and could be considered as a lead compound for developing Aβ42 specific PET tracers.