Neural Stem Cell-Derived Exosomes Revert HFD-Dependent Memory Impairment via CREB-BDNF Signalling.

Matteo Spinelli,Claudio Grassi,Salvatore Fusco,Lucia Leone,Francesca Natale,Daniele Mezzogori,Marco Rinaudo

doi:10.3390/ijms21238994

Abstract

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.

Highlights

The central nervous system undergoes structural and functional changes throughout adulthood in response to physiological stimuli and environmental conditions
We recently reported that high fat diet (HFD) affects hippocampal synaptic plasticity and memory by inhibiting the early phase of long-term potentiation (LTP) via AMPA receptor GluA1 hyper-palmitoylation [22]
A real-time PCR (RT-PCR) array revealed up- and downregulation of several genes in the hippocampus of overfed mice, including matrix metallopeptidase 9 (Mmmp9, +377%), neurotrophin 5 (Ntf5, +242%), Bdnf (−77%), discs large homolog 4 (Dlg4, −65%), early growth response 3 (Egr3, −65%), glutamate receptor interacting protein 1 (Grip1, −75%), glutamate metabotropic receptor 4 and 8 (Grm4 and Grm8, −74% and −70%, respectively), neuronal nitric oxide synthase, proviral integration site 1 (Pim1, −76%), v-rel reticuloendotheliosis viral oncogene homolog A (RelA, −66%) and sirtuin 1 (Sirt1, −75%) (n = 4 mice; Figure 1 and Supplementary Table S1)

Summary

Introduction

The central nervous system undergoes structural and functional changes throughout adulthood in response to physiological stimuli and environmental conditions. Neuroplasticity involves proliferation and differentiation of adult neural stem cells as well as changes in the morphology and activity of differentiated neurons [1]. Environmental stimuli influence the physiology of brain cells by regulating the expression of large numbers of specific gene sets via epigenetic modifications [2]. Overnutrition alters normal cell signalling in the brain, potentially interfering with both synaptic function and adult neurogenesis, thereby leading to impairment of cognitive functions [3]. The molecular mechanisms underlying the long-term effects of nutrient excess on synaptic plasticity and memory are still partially unknown

Methods

Results

Conclusion