Therapeutic potential and underlying mechanisms of engineered young plasma-derived exosomes in Alzheimer's disease.

Abstract

Exosomes (EXOs) derived from the plasma of young individuals are believed to have the potential to ameliorate aging-related memory deficits. However, their specific roles and mechanisms in Alzheimer's disease (AD) therapy have not yet been systematically investigated. In this study, the rabies virus glycoprotein-targeting peptide (RVG-29) was conjugated to the surface of young plasma-derived EXOs to construct RVG-engineered EXOs (RVG-EXOs), and their therapeutic potential and underlying mechanisms in AD models were systematically evaluated. In 3×Tg AD model mice, exogenous administration of young plasma-derived EXOs and their engineered product (RVG-EXOs) revealed that RVG-EXOs could more efficiently enter brain tissue and target neurons, significantly reduce Aβ plaque and phosphorylated Tau (P-Tau) pathological deposition, restore synaptic structure, promote neuronal survival, and improve cognitive behavior. Mechanistic studies demonstrated that RVG-EXOs inhibited <i>RPTOR</i> expression, thereby activating the autophagy pathway and promoting the clearance of pathological proteins. Both in vitro and in vivo experiments confirmed that overexpression of <i>RPTOR</i> significantly suppressed the therapeutic effects of RVG-EXOs. single-cell transcriptomic profiling further revealed that RVG-EXOs not only increased neuronal proportion and modulated excitatory/inhibitory neuronal balance but also reshaped the microglial landscape by reducing deleterious disease-associated while increasing homeostatic surveillant microglia. In summary, this study not only reveals for the first time the potential value of young plasma-derived EXOs in AD treatment but also, through RVG engineering strategies and the elucidation of the <i>RPTOR</i>-autophagy mechanism, provides new insights for targeted therapy of neurodegenerative diseases.