Extracellular Vesicles Derived from Tobacco BY-2 Cells Exert Anti-Alzheimer’s Effect by Stimulating Astrocytes to Degrade Aβ

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that seriously affects the quality of life in the elderly. The abnormal aggregation of beta-amyloid (Aβ) is a critical driving factor of AD. Tobacco contains various active molecules with neuroprotective effects, which influence the aggregation of Aβ and demonstrate potential for AD treatment in clinical data analysis. Plant-derived extracellular vesicles carry bioactive molecules from their parental cells and exhibit unique advantages in disease therapy due to their natural biocompatibility and low immunogenicity. We isolated extracellular vesicles (tEVs) from tobacco BY-2 cells, detected that they contained abundant components such as proteins, lipids, and metabolites, and proposed that the high levels of HSP70 and pyruvate dehydrogenase enzyme could serve as markers for identifying tEVs. Animal experimental studies showed that tEVs entered the brain via the nasal route and were taken up by astrocytes, reduced the deposition of Aβ plaques in the cortex and hippocampal regions of the brain, decreased the overall Aβ content, and improved the impaired learning and memory abilities of 5xFAD mice. Further studies found that tEVs led to an increase in the phosphorylation expression of PI3K and AKT in astrocytes, upregulated the production of endogenous αB-crystallin protein (Cryab), and reduced the aggregation and content levels of Aβ both within and outside of the cells. These tEV-mediated changes were reversed by pre-treatment with the PI3K/AKT signaling pathway inhibitor LY294002. These findings indicate that tEVs promote the degradation of Aβ by astrocytes via the PI3K/AKT signaling pathway and exert anti-AD effects. tEVs are a promising anti-AD therapeutic drug.