Intranasal administration of neural stem cell-derived extracellular vesicles prevents cognitive decline in both male and female 3×Tg-AD mice by dampening neuroinflammation and epigenetically regulating amyloid β metabolism

Background: Alzheimer’s disease (AD) is the leading cause of dementia in the elderly and poses a significant socioeconomic burden due to its progressive nature and lack of effective treatments. Recent studies suggest that neural stem cell-derived extracellular vesicles (NSC-EV) hold therapeutic potential against AD by delivering bioactive molecules that counteract neuroinflammation, oxidative stress, and protein dysregulation. Methods: NSC-EV were intranasally administered to both male and female 3×Tg-AD mice from three to twelve months of age and cognitive function were evaluated at multiple time points. Moreover, neuroinflammation and amyloid-β (Aβ) metabolism markers were studied at 9 months of age. Results: Intranasal administration of NSC-EV delayed cognitive decline, reduced hippocampal neuroinflammation, and decreased Aβ accumulation in both male and female 3×Tg-AD mice. These functional effects were accompanied by the downregulation of STAT5 expression, which is a mediator of neuroinflammatory signaling, and the upregulation of neuroprotective transcription factor NRF2. Moreover, the changes in STAT5 and NRF2 expression caused the epigenetic inhibition of pro-amyloidogenic beta secretase BACE1 transcription and the enhanced expression of IDE, which is the main enzyme involved in Aβ clearance. These events were accompanied by the reduction of Aβ levels. Conclusions: Our findings provide new insights into the molecular mechanisms by which NSC-EV modulate AD pathology and support their potential as a regenerative therapy for neurodegenerative diseases.