Department of Neuroscience, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy.
Int J Mol Sci. 2020 Nov 26;21(23):8994. doi: 10.3390/ijms21238994.
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 element-binding 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.
营养过剩和代谢紊乱通过分子机制损害认知功能，但这些机制仍知之甚少。我们在高脂饮食（HFD）喂养的小鼠中分析了与突触可塑性相关的基因表达和环磷酸腺苷反应元件结合蛋白（CREB）-脑源性神经营养因子（BDNF）-原肌球蛋白受体激酶 B（TrkB）信号通路的激活情况。我们发现，HFD 抑制了海马体中 CREB 磷酸化和一组 CREB 靶基因的表达。神经干细胞（NSC）衍生的外泌体（exo-NSC）经鼻给药通过诱导 CREB 募集到其调节序列上，从而表观遗传地上调了 Bdnf、nNOS、Sirt1、Egr3 和 RelA 基因的转录。最后，exo-NSC 给药挽救了 HFD 小鼠的 BDNF 信号和记忆。总的来说，我们的研究结果强调了与 HFD 相关的记忆损伤的新机制，并为 exo-NSC 对抗代谢性疾病相关认知能力下降的潜在治疗效果提供了证据。
