Human neural stem cell transplantation improves cognition in a murine model of Alzheimer’s disease

Abstract

Stem cell transplantation offers a potentially transformative approach to treating neurodegenerative disorders. The safety of cellular therapies is established in multiple clinical trials, including our own in amyotrophic lateral sclerosis. To initiate similar trials in Alzheimer’s disease, efficacious cell lines must be identified. Here, we completed a preclinical proof-of-concept study in the APP/PS1 murine model of Alzheimer’s disease. Human neural stem cell transplantation targeted to the fimbria fornix significantly improved cognition in two hippocampal-dependent memory tasks at 4 and 16 weeks post-transplantation. While levels of synapse-related proteins and cholinergic neurons were unaffected, amyloid plaque load was significantly reduced in stem cell transplanted mice and associated with increased recruitment of activated microglia. In vitro, these same neural stem cells induced microglial activation and amyloid phagocytosis, suggesting an immunomodulatory capacity. Although long-term transplantation resulted in significant functional and pathological improvements in APP/PS1 mice, stem cells were not identified by immunohistochemistry or PCR at the study endpoint. These data suggest integration into native tissue or the idea that transient engraftment may be adequate for therapeutic efficacy, reducing the need for continued immunosuppression. Overall, our results support further preclinical development of human neural stem cells as a safe and effective therapy for Alzheimer’s disease.

Effects of neural stem cell transplantation in Alzheimer’s disease models

“…This was not mentioned in the 3xTg and Tg2576 models. Conversely, another study showed that NSC transplantation has no effect on synaptic density, but that it does improve behaviour [54]. An opposite long-term result in transplanting hNSC into RAG-5xfAD were obtain from two studies.…”

“…In 2018, a study by McGinley suggested that transplanted hNSCs regulate microglial activation and thus reduces Aβ levels. Furthermore, the beneficial effect of the treatment on behaviour lasted for 4 months after transplantation [54] (Table 3).…”

“…Some partially contradicting results have been obtained. In one study, hNSCs rescued cognitive deficits without altering synaptic density [54], while in another, hNSCs improved synaptic density and neural metabolic activity, but mitigated behavioural improvement [53]. In some studies, hNSC transplantation activated microglia and decreased Aβ level [54], while a review of mNSC studies found no change in Aβ levels, although cognitive deficits were rescued.…”

“…In one study, hNSCs rescued cognitive deficits without altering synaptic density [54], while in another, hNSCs improved synaptic density and neural metabolic activity, but mitigated behavioural improvement [53]. In some studies, hNSC transplantation activated microglia and decreased Aβ level [54], while a review of mNSC studies found no change in Aβ levels, although cognitive deficits were rescued. The decrease in pro-inflammatory factors [58], neuron replacement, increase in cognitive related protein [60] and rise in effective neuronal transmitter levels [59] contributed to this outcome.…”

Stem Cell-Based Disease Modeling and Cell Therapy

“…Stem cell-based therapies are defined as any treatment for a disease or a medical condition that fundamentally involves the use of any type of viable human stem cells including ESCs, iPSCs, and adult stem cells for autologous and allogeneic therapies. Emerging evidence of stem cell-based therapeutic effects from preclinical and clinical studies suggest that regenerative strategies may one day become a treatment for a wide range of vexing diseases [ 46 , 47 , 48 , 49 ]. The current progress of therapies using various stem cells such as MSCs (e.g., ADSCs and BM-MSCs), urine-derived stem cells, iPSCs, and spermatogonial stem cells (SSCs) are described and discussed in this Special Issue.…”