A Nature-Inspired Steroid-like Electron Acceptor to Polarity-Dependent Probe for Visualizing Lipid Evolution in Alzheimer's Disease.

Abstract

Current petrochemical-based electron acceptors in advanced optical materials face problems such as structural diversity, renewability, and biocompatibility. Natural product-derived fluorescent materials with donor-acceptor structures, stimuli-responsive photophysical properties, and superior biocompatibility are crucial for biomedical applications like visualizing the lipid evolution in Alzheimer's disease (AD). In this work, a nature-inspired electron acceptor (DABT) analogous to steroids has been constructed based on the tricyclic diterpene skeleton of natural rosin. Through substitution with variable electron donors, the dimethyl amino-substituted compound, DABT-DMA, can be applied as a polarity-dependent biosensor with dual-stimuli responsiveness of distinct fluorescence wavelength and lifetime. The natural skeleton's advantageous biocompatibility and targeting capability enable lipid droplet-targeted imaging. Further investigations prove that the single biobased sensor can combine the bilateral advantages of two commercial probes, confirming that Aβ protein-induced lipid droplet dysfunction causes cholesterol analogue accumulation, worsening AD pathology. This work not only proposes a steroid-like natural electron acceptor with both biocompatibility and targeting capability but also offers insights into AD-related pathophysiological mechanisms.