A mitochondria targeting, de novo designed, aggregation-induced emission probe for selective detection of neurotoxic...

A striking issue is the scarcity of imaging probes for the early diagnosis of Alzheimer's disease. For the development of Aβ biomarkers, a mitochondria targeting, de novo designed, 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 with monomeric Aβ40 with a high binding affinity (K_d = 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⁺ (λ_em 604 nm) selectively targets and images neuronal cell mitochondria, is useful to monitor mitochondrial morphology alteration and damage during Aβ40-induced neurotoxicity, recognizes neurotoxic Aβ fibrils, and is highly colocalized with thioflavin T, showing a decent Pearson 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.