The role of plant-derived extracellular vesicles on the in vitro Alzheimer's disease model

Alzheimer's disease is a progressive and irreversible neurodegenerative disorder, in which the accumulation of amyloid beta (Aβ) peptides and the hyperphosphorylation of tau proteins play a pivotal role in its pathogenesis. Current treatment methods mostly aim to alleviate symptoms, but are insufficient in stopping disease progression or targeting the underlying mechanisms. Extracellular vesicles (EVs) are nanovesicles that provide intercellular communication, have a lipid bilayer membrane structure, and can carry biomolecules such as proteins, lipids, and RNA. Lately, EVs have gained significant interest as therapeutic tools due to their effects such as regulating gene expression, suppressing inflammation, and triggering cellular repair processes in disease models. Plant-derived EVs (PDEVs) stand out as important biotherapeutic candidates due to their natural origin, low immunogenicity, economical production, and cross-species biological activity. In addition, their anti- inflammatory and antioxidant properties make EVs attractive candidates for targeting neurodegenerative pathways. This study aims to investigate the effects of extracellular vesicles isolated from tobacco (Nicotiana tabacum) (TEV) suspension culture and celery (Apium graveolens) extract (CEV) in an in vitro AD model. In the study, Aβ accumulation and hyperphosphorylation of tau proteins were induced in differentiated SH-SY5Y cells and an AD-like model was created by treating neurons with TEV, while astrocytes were treated with CEV in a gliotic model created by applying Aβ peptide. Molecular and cellular analyses performed after the application showed that TEV application reduced neuronal degeneration, while CEV application suppressed Aβ-induced astrogliosis responses. In particular, a significant decrease was observed in Aβ and phospho-tau accumulations and protein aggregate load. The findings suggest that PDEVs may affect AD pathophysiology and have neuroprotective potential on both neuronal and glial targets. This study is the first to explore the therapeutic potential of PDEVs in AD, laying an important foundation for future research in this field.