Neural stem cell‐derived exosomes revert HFD-dependent memory impairment via CREB‐BDNF signalling

Overnutrition and metabolic disorders impair cognitive functions through molecular mechanisms still poorly understood. In mice fed with a high fat diet (HFD) we analysed the expression of synaptic plasticity‐related genes and the activation of cAMP response elementbinding protein (CREB)‐brain‐derived neurotrophic factor (BDNF)‐tropomyosin receptor kinase B (TrkB) signalling. We found that a HFD inhibited both CREB phosphorylation and the expression of a set of CREB target genes in the hippocampus. The intranasal administration of neural stem cell (NSC)‐derived exosomes (exo‐NSC) epigenetically restored the transcription of Bdnf, nNOS, Sirt1, Egr3, and RelA genes by inducing the recruitment of CREB on their regulatory sequences. Finally, exo‐NSC administration rescued both BDNF signalling and memory in HFD mice. Collectively, our findings highlight novel mechanisms underlying HFD‐related memory impairment and provide evidence of the potential therapeutic effect of exo‐NSC against metabolic disease‐related cognitive decline