Dual Targeted Far-Red Emissive Small Molecules for Mitochondrial Imaging and Multifunctional Modulation in Alzheimer's Disease.

Abstract

Alzheimer's disease (AD), the leading cause of age-related dementia, is a multifactorial neurodegenerative disorder associated with amyloid-β (Aβ) aggregation, metal ion dyshomeostasis, oxidative stress, and mitochondrial dysfunction. The pathological interplay among these processes necessitates multifunctional small molecules capable of both diagnosis and therapeutic intervention. Herein, we report two triphenylamine (TPA)-based aggregation-induced emission (AIE) luminogens, TPA-RPA (triphenylamine-rhodaninepropanoic acid) and TPA-ER (triphenylamine-ethylrhodanine), designed as mitochondria-active anti-amyloid theranostic agents. Among them, TPA-RPA emerged as the lead candidate, exhibiting far-red emission and a pronounced ∼5-fold fluorescence turn-on response upon selective binding to Aβ40 fibrils, enabling sensitive detection of pathogenic aggregates. TPA-RPA effectively inhibited Aβ40 fibrillogenesis, disaggregated preformed fibrils, binds with selective metal ions Fe³⁺/Cu²⁺, and suppressed Fe³⁺ mediated amyloid aggregation, highlighting its multifunctional anti-amyloid activity. In neuronal cells, TPA-RPA displayed favorable biocompatibility, appreciable mitochondrial localization, and significant protection against Aβ-induced cytotoxicity, oxidative stress, and mitochondrial dysfunction. Comparative studies identified TPA-ER as a useful analog with a stronger but more pronounced oxidative response, while TPA-RPA demonstrated the most balanced overall biological profile, establishing it as a synthetically accessible and mechanistically versatile platform for image-guided intervention in AD, supported by photophysical, cellular, in silico molecular docking analyses, and blood-brain barrier/drug-likeness evaluations.