A β-sheet-targeted theranostic agent for diagnosing and preventing aggregation of pathogenic peptides in Alzheimer’s disease

Abstract

Amyloid-β peptide (Aβ) aggregates, particularly Aβ oligomers, are established biomarker and toxic species in Alzheimer’s disease (AD). Early detection and disaggregation of Aβ aggregates are of great importance for the treatment of AD due to the unavailability of therapy at the advanced stages of the disease. A multitalented agent, 2-{2-[(1 H -benzoimidazol-2-yl)methoxy]phenyl}benzothiazole (BPB), is designed by merging two β-sheet targeting groups into one molecule to detect and inhibit the Aβ aggregation. BPB can quantitatively measure the β-sheet level of soluble Aβ oligomers and specifically distinguish the aggregates of Aβ40 and Aβ42 by unique luminescence spectrum. Animal tests demonstrate that BPB can efficiently penetrate the blood brain barrier and precisely stain Aβ plaques in the brain; more importantly, it can differentiate the blood of APP transgenic mice from that of normal ones. In addition to the diagnostic potential, BPB also suppresses the generation of ROS, protects the neurons from neurotoxicity, and disaggregates the Aβ aggregates in brain homogenates of APP transgenic mice induced by metal ions or self-assembly. In view of its detective ability toward Aβ oligomers and inhibition to Aβ-related neurotoxicity, BPB may be developed into a sensitive probe for screening blood samples in the early diagnosis of AD as well as an effective inhibitor for diminishing Aβ aggregates in the treatment of the disease.