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

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

doi:10.3390/ijms21238994

Cited by 21 publications

(18 citation statements)

References 51 publications

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“…27 We recently demonstrated that exo-NSPC containing BDNF rescued TrkB activation in the hippocampus of insulin resistant mice. 16 However, in NSPCs the level of TrkB phosphorylation was not significantly changed upon IPA treatment nor following administration of exo-NSPC (F 6.94 = 0.504, n = 3; Fig. 5A).…”

Section: Exo-nspc Reactivate Foxo Transcriptional Activity In Insulin...mentioning

confidence: 86%

“…14,42 We recently discovered that exo-NSPC carry neurotrophic factors able to modulate signal transduction and gene expression in neurons. 16 However, the BDNF/TrkB/CREB axis does not appear to play a prominent role in the effects of both insulin resistance and exo-NSPC on NSPCs (Figs. 3A and 5A).…”

Section: Discussionmentioning

confidence: 97%

“…We recently reported the ability of exosomal vesicles derived from NSPCs (exo-NSPC) to counteract the detrimental effects of insulin resistance on cognitive function by interfering with the gene expression in differentiated neurons. 16 Therefore, we asked whether exo-NSPC also exerted a beneficial effect on the neurogenic niche by counteracting the IPA-dependent impairment of NSPC proliferation. First, we characterized vesicles purified from NSPC culture media using transmission electron microscopy, dynamic light scattering, and immunoblot analysis (Supplementary Fig.…”

Section: Nspc-derived Exosomes Rescue Proliferation/ Senescence Balan...mentioning

confidence: 99%

“…[13][14][15] We recently demonstrated that NSPC-derived exosomes (exo-NSPC) rescued BDNF-TrkB signaling in the hippocampus and reverted memory deficits in a mouse model of brain insulin resistance (BIR). 16 Therefore, we investigated whether exo-NSPC also affected NSPC pool and adult hippocampal neurogenesis in a well-established mouse model of BIR-dependent cognitive impairment, such as mice fed a high-fat diet (HFD). 17 Here, we demonstrated that HFD reduced NSPC proliferation and promoted senescence of self-renewing cells.…”

Section: Introductionmentioning

confidence: 99%

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Neural Stem Cell-Derived Extracellular Vesicles Counteract Insulin Resistance-Induced Senescence of Neurogenic Niche

et al. 2022

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Neural stem and progenitor cell (NSPC) depletion may play a crucial role in the cognitive impairment observed in many age-related non communicable diseases. Insulin resistance affects brain functions through a plethora of mechanisms that remain poorly understood. In an experimental model of insulin resistant NSPCs, we identified a novel molecular circuit relying on Insulin receptor substrate 1 (IRS1)/Forkhead box O (FoxO) signaling cascade and inhibiting the recruitment of transcription factors FoxO1 and FoxO3a on the promoters of genes regulating proliferation and self-renewal. Insulin resistance also epigenetically increased the expression of cyclin-dependent kinase inhibitor 1 (p21) and accelerated NSPC senescence. Of note, we found that stimulation of NSPCs with NSPC-derived exosomes (exo-NSPC) rescued IRS1/FoxO activation and counteracted both the reduced proliferation and senescence of stem cells. Accordingly, intranasal administration of exo-NSPC counteracted the high fat diet-dependent impairment of adult hippocampal neurogenesis in mice by restoring the balance between proliferating and senescent NSPCs in the hippocampus. Our findings suggest a novel mechanism underlying the metabolic control of NSPC fate potentially involved in the detrimental effects of metabolic disorders on brain plasticity. In addition, our data highlight the role of extracellular vesicle-mediated signals in the regulation of cell fate within the adult neurogenic niche.

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Section: Exo-nspc Reactivate Foxo Transcriptional Activity In Insulin...mentioning

confidence: 86%

Section: Discussionmentioning

confidence: 97%

Section: Nspc-derived Exosomes Rescue Proliferation/ Senescence Balan...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neural Stem Cell-Derived Extracellular Vesicles Counteract Insulin Resistance-Induced Senescence of Neurogenic Niche

et al. 2022

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“…To further exclude place preference for one side of the arena, the position of the novel object was alternated on both sides for the different testing sessions. The objects and arena were cleaned with a 70% ethanol solution between the subsequent tests [ 23 ].…”

Section: Methodsmentioning

confidence: 99%

Hippocampal Estrogen Signaling Mediates Sex Differences in Retroactive Interference

et al. 2022

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Despite being a crucial physiological function of the brain, the mechanisms underlying forgetting are still poorly understood. Estrogens play a critical role in different brain functions, including memory. However, the effects of sex hormones on forgetting vulnerabilitymediated by retroactive interference (RI), a phenomenon in which newly acquired information interferes with the retrieval of already stored information, are still poorly understood. The aim of our study was to characterize the sex differences in interference-mediated forgetting and identify the underlying molecular mechanisms. We found that adult male C57bl/6 mice showed a higher susceptibility to RI-dependent memory loss than females. The preference index (PI) in the NOR paradigm was 52.7 ± 5.9% in males and 62.3 ± 13.0% in females. The resistance to RI in female mice was mediated by estrogen signaling involving estrogen receptor α activation in the dorsal hippocampus. Accordingly, following RI, females showed higher phosphorylation levels (+30%) of extracellular signal-regulated kinase1/2 (ERK1/2) in the hippocampus. Pharmacological inhibition of ERK1/2 made female mice prone to RI. The PI was 70.6 ± 11.0% in vehicle-injected mice and 47.4 ± 10.8% following PD98059 administration. Collectively, our data suggest that hippocampal estrogen α receptor-ERK1/2 signaling is critically involved in a pattern separation mechanism that inhibits object-related RI in female mice.

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Neural stem/progenitor cell‐derived extracellular vesicles: A novel therapy for neurological diseases and beyond

Zhu

Wang

et al. 2023

MedComm

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As bilayer lipid membrane vesicles secreted by neural stem/progenitor cells (NSCs), NSC-derived extracellular vesicles (NSC-EVs) have attracted growing attention for their promising potential to serve as novel therapeutic agents in treatment of neurological diseases due to their unique physicochemical characteristics and biological functions. NSC-EVs exhibit advantages such as stable physical and chemical properties, low immunogenicity, and high penetration capacity to cross blood-brain barrier to avoid predicaments of the clinical applications of NSCs that include autoimmune responses, ethical/religious concerns, and the problematic logistics of acquiring fetal tissues. More importantly, NSC-EVs inherit excellent neuroprotective and neuroregenerative potential and immunomodulatory capabilities from parent cells, and display outstanding therapeutic effects on mitigating behavioral alterations and pathological phenotypes of patients or animals with neurological diseases. In this review, we first comprehensively summarize the progress in functional research and application of NSC-EVs in different neurological diseases, including neurodegenerative diseases, acute neurological diseases, dementia/cognitive dysfunction, and peripheral diseases. Next, we provide our thoughts on current limitations/concerns as well as tremendous potential of NSC-EVs in clinical applications. Last, we discuss future directions of further investigations on NSC-EVs and their probable applications in both basic and clinical research.

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

Cited by 21 publications

References 51 publications

Neural Stem Cell-Derived Extracellular Vesicles Counteract Insulin Resistance-Induced Senescence of Neurogenic Niche

Neural Stem Cell-Derived Extracellular Vesicles Counteract Insulin Resistance-Induced Senescence of Neurogenic Niche

Hippocampal Estrogen Signaling Mediates Sex Differences in Retroactive Interference

Neural stem/progenitor cell‐derived extracellular vesicles: A novel therapy for neurological diseases and beyond

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