An aggregation-induced emission-active theranostic agent for selectively detecting and intervening pathological Tau protein

The accumulation of Tau aggregates is commonly linked with various neurodegenerative diseases, such as Alzheimer's disease, Pick's disease, and corticobasal degeneration. Notwithstanding substantial investments in the development of clinical strategies for effective intervention, traditional design paradigms are predominantly confined to molecules featuring either a solitary function or single-dimensional mode of intervention, ignoring the necessity of personalized and precise medicine. Herein, we design and synthesize a dual-functional aggregation-induced emission-active agent to serve as both a fluorescent probe for the imaging of pathological Tau and a modulator for intervention. This amphiphilic theranostic agent, named TPE-P9, is prepared <i>via</i> a one-pot Michael reaction between hydrophobic maleimide-modified tetraphenylethylene (TPE-Mal) and a hydrophilic cysteine-modified Tau-targeting peptide (CKVQIINKK). Microscale thermophoresis measurement and <i>in vitro</i> fluorescence analysis demonstrate that TPE-P9 exhibits specific binding affinity (<i>K</i>_d = 4.46 µM) and high selectivity towards Tau fibrils, featuring a pronounced low background interference, which is superior to the classical amyloid protein probe thioflavin T (ThT). At the living cellular level, TPE-P9 is capable of readily imaging endogenic pathological Tau to distinguish normal neurons from the lesional neurons <i>in situ</i>, and the staining consequence is almost consistent with that of ThT. On the other hand, as a modulator, TPE-P9 can potently protect neurons from cytotoxic Tau-induced apoptosis both by inhibiting aberrant post-translational modification-induced Tau self-assembly and by blocking the produced pathological Tau propagation, enhancing cell viability by 35.4%. These findings offer valuable insights for the development of innovative image-guided therapeutic strategies for targeted tauopathies treatment.