Environment-Sensitive Near-Infrared Probe for Fluorescent Discrimination of Aβ and Tau Fibrils in AD Brain

The early noninvasive diagnosis of Alzheimer’s disease targeted β-amyloid (Aβ) plaques or Tau tangles is a major challenge because of the coshared β-sheet structure of the target. In contrast to tailoring probes to specific amyloids, here, we showed that near-infrared (NIR) environment-sensitive probe 18 could fluorescently discriminate Aβ and Tau from artificial aggregates to pathological change in the brain tissue. The biological evaluation demonstrated that the substantial fluorescence enhancement, large blueshift in the emission upon interactions with the aggregates, and the high binding affinity significantly contributed to the fluorescent discrimination. A simplified Ooshika–Lippert–Mataga equation provided an effective means of correlating 18 with the static relative permittivity (ε0) of proteins, elucidating the origin of the distinction capabilities, and quantitatively estimating the dielectric properties of proteins. Moreover, 18 possessed high bioavailability, including sufficient blood–brain barrier penetration, in vivo NIR imaging, and ex vivo histology in living mice.