Human neural stem cells alleviate Alzheimer-like pathology in a mouse model

Abstract

BackgroundAlzheimer’s disease (AD) is an inexorable neurodegenerative disease that commonly occurs in the elderly. The cognitive impairment caused by AD is associated with abnormal accumulation of amyloid-β (Aβ) and hyperphosphorylated tau, which are accompanied by inflammation. Neural stem cells (NSCs) are self-renewing, multipotential cells that differentiate into distinct neural cells. When transplanted into a diseased brain, NSCs repair and replace injured tissues after migration toward and engraftment within lesions. We investigated the therapeutic effects in an AD mouse model of human NSCs (hNSCs) that derived from an aborted human fetal telencephalon at 13 weeks of gestation. Cells were transplanted into the cerebral lateral ventricles of neuron-specific enolase promoter-controlled APPsw-expressing (NSE/APPsw) transgenic mice at 13 months of age.ResultsImplanted cells extensively migrated and engrafted, and some differentiated into neuronal and glial cells, although most hNSCs remained immature. The hNSC transplantation improved spatial memory in these mice, which also showed decreased tau phosphorylation and Aβ42 levels and attenuated microgliosis and astrogliosis. The hNSC transplantation reduced tau phosphorylation via Trk-dependent Akt/GSK3β signaling, down-regulated Aβ production through an Akt/GSK3β signaling-mediated decrease in BACE1, and decreased expression of inflammatory mediators through deactivation of microglia that was mediated by cell-to-cell contact, secretion of anti-inflammatory factors generated from hNSCs, or both. The hNSC transplantation also facilitated synaptic plasticity and anti-apoptotic function via trophic supplies. Furthermore, the safety and feasibility of hNSC transplantation are supported.ConclusionsThese findings demonstrate the hNSC transplantation modulates diverse AD pathologies and rescue impaired memory via multiple mechanisms in an AD model. Thus, our data provide tangible preclinical evidence that human NSC transplantation could be a safe and versatile approach for treating AD patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-015-0035-6) contains supplementary material, which is available to authorized users.

Human Neural Stem Cell Transplantation Rescues Cognitive Defects in APP/PS1 Model of Alzheimer’s Disease by Enhancing Neuronal Connectivity and Metabolic Activity

“…Recently, emerging studies reported transplantation of hNSCs in mice with various disease models (Lee I.-S. et al, 2015; Zuo et al, 2015; Haus et al, 2016). While some studies reported the differentiation failure of engrafted hNSCs in mice (Lee S.-R. et al, 2015), more studies showed the predominant differentiation of hNSCs into astrocytes (Gao et al, 2006; Lee I.-S. et al, 2015). The different differentiation patterns could be associated with the source of human cells, cell preparation, as well as difference in animal models.…”

“…Cell rejection is an ongoing issue challenging the NSC transplantation therapy especially for using xenogeneic transplants (Lee I.-S. et al, 2015). Due to difference in cell sources and transplantation sites, the survival and differentiation rates of implanted xenogeneic NSCs are differently reported across studies (Ager et al, 2015; Haus et al, 2016).…”

“…Due to difference in cell sources and transplantation sites, the survival and differentiation rates of implanted xenogeneic NSCs are differently reported across studies (Ager et al, 2015; Haus et al, 2016). Some studies reported the injection of immunosuppressive drugs in combination with cell transplantation to enhance the survival of xenogeneic NSCs (Ager et al, 2015; Lee I.-S. et al, 2015). In this study, however, we injected hNSCs into the hippocampus of AD mice without addition of immunosuppressive agents.…”

Human neural stem cell transplantation into the corpus callosum of Alzheimer's mice

“…Cellular therapies represent a potential disease‐modifying treatment for Alzheimer's disease (AD), with multifaceted therapeutic benefits including tissue replacement, secretion of neuroprotective trophic factors, and/or modulation of inflammation 1, 2, 3, 4, 5, 6. As such, transplantation of stem cells from various sources into the hippocampus improves cognitive impairment in murine AD models 1, 7, 8.…”

Cell-based therapy in Alzheimer's disease: Current knowledge and perspective

“…In fact, transplanted cells modulate diverse AD pathologies and rescue impaired memory via multiple mechanisms in an AD model [76,77] .…”