Dataset Information

Human umbilical cord mesenchymal stem cell-derived neuron-like cells rescue memory deficits and reduce amyloid-beta deposition in an A?PP/PS1 transgenic mouse model.

ABSTRACT:

Introduction

Cell therapy is a potential therapeutic approach for neurodegenerative disorders, such as Alzheimer disease (AD). Neuronal differentiation of stem cells before transplantation is a promising procedure for cell therapy. However, the therapeutic impact and mechanisms of action of neuron-like cells differentiated from human umbilical cord mesenchymal stem cells in AD have not been determined.

Methods

In this study, we used tricyclodecan-9-yl-xanthogenate (D609) to induce human mesenchymal stem cells isolated from Wharton jelly of the umbilical cord (HUMSCs) to differentiate into neuron-like cells (HUMSC-NCs), and transplanted the HUMSC-NCs into an A?PP/PS1 transgenic AD mouse model. The effects of HUMSC-NC transplantation on the cognitive function, synapsin I level, amyloid ?-peptides (A?) deposition, and microglial function of the mice were investigated.

Results

We found that transplantation of HUMSC-NCs into A?PP/PS1 mice improved the cognitive function, increased synapsin I level, and significantly reduced A? deposition in the mice. The beneficial effects were associated with "alternatively activated" microglia (M2-like microglia). In the mice transplanted with HUMSC-NCs, M2-like microglial activation was significantly increased, and the expression of antiinflammatory cytokine associated with M2-like microglia, interleukin-4 (IL-4), was also increased, whereas the expression of proinflammatory cytokines associated with classic microglia (M1-like microglia), including interleukin-1? (IL-1?) and tumor necrosis factor-? (TNF-?), was significantly reduced. Moreover, the expression of A?-degrading factors, insulin-degrading enzyme (IDE) and neprilysin (NEP), was increased substantially in the mice treated with HUMSC-NCs.

Conclusions

HUMSC-NC transplantation decreased A? deposition and improved memory in A?PP/PS1 mice by a mechanism associated with activating M2-like microglia and modulating neuroinflammation. Transplantation of neuron-like cells differentiated from mesenchymal stem cells might be a promising cell therapy for Alzheimer disease.

SUBMITTER: Yang H

PROVIDER: S-EPMC3854736 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Human umbilical cord mesenchymal stem cell-derived neuron-like cells rescue memory deficits and reduce amyloid-beta deposition in an AβPP/PS1 transgenic mouse model.

Yang Hui H Xie ZhaoHong Z Wei LiFei L Yang HongNa H Yang ShaoNan S Zhu ZhengYu Z Wang Ping P Zhao CuiPing C Bi JianZhong J

Stem cell research & therapy 20130704 4

<h4>Introduction</h4>Cell therapy is a potential therapeutic approach for neurodegenerative disorders, such as Alzheimer disease (AD). Neuronal differentiation of stem cells before transplantation is a promising procedure for cell therapy. However, the therapeutic impact and mechanisms of action of neuron-like cells differentiated from human umbilical cord mesenchymal stem cells in AD have not been determined.<h4>Methods</h4>In this study, we used tricyclodecan-9-yl-xanthogenate (D609) to induce ...[more]

PMID: 23826983

Similar Datasets

Project description:Alzheimer's disease (AD) underlies dementia for millions of people worldwide, and its occurrence is set to double in the next 20 years. Currently, approved drugs for treating AD only marginally ameliorate cognitive deficits, and provide limited symptomatic relief, while newer substances under therapeutic development are potentially years away from benefiting patients. Melatonin (MEL) for insomnia has been proven safe with >15 years of over-the-counter access in the US. MEL exerts multiple complementary mechanisms of action against AD in animal models; thus it may be an excellent disease-modifying therapeutic. While presumed to provide neuroprotection via activation of known G-protein-coupled melatonin receptors (MTNRs), some data indicate MEL acts intracellularly to protect mitochondria and neurons by scavenging reactive oxygen species and reducing free radical formation. We examined whether genetic deletion of MTNRs abolishes MEL's neuroprotective actions in the A?PP(swe)/PSEN1dE9 mouse model of AD (2xAD). Beginning at 4 months of age, both AD and control mice either with or without both MTNRs were administered either MEL or vehicle in drinking water for 12 months.Behavioral and cognitive assessments of 15-month-old AD mice revealed receptor-dependent effects of MEL on spatial learning and memory (Barnes maze, Morris Water Maze), but receptor-independent neuroprotective actions of MEL on non-spatial cognitive performance (Novel Object Recognition Test). Similarly, amyloid plaque loads in hippocampus and frontal cortex, as well as plasma A?1-42 levels, were significantly reduced by MEL in a receptor-independent manner, in contrast to MEL's efficacy in reducing cortical antioxidant gene expression (Catalase, SOD1, Glutathione Peroxidase-1, Nrf2) only when receptors were present. Increased cytochrome c oxidase activity was seen in 16 mo AD mice as compared to non-AD control mice. This increase was completely prevented by MEL treatment of 2xAD/MTNR+ mice, but only partially prevented in 2xAD/MTNR- mice, consistent with mixed receptor-dependent and independent effects of MEL on this measure of mitochondrial function.These findings demonstrate that prophylactic MEL significantly reduces AD neuropathology and associated cognitive deficits in a manner that is independent of antioxidant pathways. Future identification of direct molecular targets for MEL action in the brain should open new vistas for development of better AD therapeutics.