Mitochondria Targeted De Novo Designed Aggregation-Induced Emission Probe for Selective Detection of Neurotoxic Amyloid‑β Aggregates

Abstract

A striking issue is the scarcity of imaging probes for the early diagnosis of Alzheimer’s disease. For the development of Aβ biomarkers, mitochondria targeting de novo designed intramolecular charge transfer-induced solvatofluorochromic aggregation-induced emission (AIE) probe Cou-AIE-TPP+ is constructed by engineering the aromatic coumarin framework into the bridge of electron donor-acceptor-donor tethered with a lipophilic cationic triphenylphosphonium (TPP+) group. The synthesized Cou-AIE-TPP+ probe exhibits biocompatibility, noncytotoxicity, and a huge Stokes shift (124 nm in PBS). Cou-AIE-TPP+ has respectable fluorescence augmentation inside the aggregated Aβ40 in comparison to monomeric Aβ40 with high binding affinity (Kd = 83 nM) to Aβ40 aggregates, is capable of detecting the kinetics of amyloid aggregation, and is superior to the gold standard probe thioflavin T. Fluorescence lifetime and brightness are also augmented when the probe Cou-AIE-TPP+ binds with Aβ aggregates in PBS. Cou-AIE-TPP+ (λem 604 nm) selectively targets and images neuronal cell mitochondria, is useful to monitor mitochondrial morphology alteration and damage during A40-induced neurotoxicity, recognizes neurotoxic Aβ fibrils, and is highly colocalized with thioflavin T, showing a decent Pearson’s correlation coefficient of 0.91 in the human neuroblastoma SH-SY5Y cell line. These findings indicate that the mitochondria targeting de novo designed functional AIE-based solvatofluorochromic Cou-AIE-TPP+ probe is a promising switch on biomarkers for fluorescence imaging of Aβ aggregates and to monitor mitochondrial morphology change and dysfunction during Aβ-induced neurotoxicity, which may offer imperative direction for the advancement of compelling AIE biomarkers for targeted early stage Aβ diagnosis in the future.