A Smart Dicyano-Based Fluorescent Probe for In Vivo Amyloid-β Visualization to Illuminate Alzheimer's Disease.

Abstract

Amyloid-β (Aβ) is a key biomarker for Alzheimer's disease (AD), with its abnormal aggregation closely linked to AD pathology. Fluorescence imaging shows promise for Aβ detection but faces challenges such as optical instability, a short blood half-life, and poor blood-brain barrier (BBB) permeability. Additionally, only a few probes could target Aβ oligomers with a higher neurotoxicity. In this study, we designed and synthesized 14 fluorescent probes using the dicyano group as an electron acceptor. Among them,emerged as the most promising probe, with a binding affinity for Aβ aggregates (= 21 nM) and strong binding to Aβ oligomers. It operates at a free-state emission wavelength of above 700 nm, offering low cytotoxicity, good serum stability, and efficient BBB permeability. In brain slice staining,robustly bound to Aβ plaques in both AD mice and human brain slices. Meanwhile,also exhibited the capability of staining Aβ oligomers in the 4 month AD brain slice. Most important,demonstrated robust imaging capabilities in AD mice of different ages and diverse AD mouse models in an in vivo study. These findings suggest thatcould be a valuable tool for understanding AD pathology and aiding diagnosis.