Development of Multi-target therapy for Alzheimer’s disease using human neural crest-derived stem cells

Abstract

Purpose Stem cell transplantation is a promising therapeutic strategy for the treatment of many neurological disorders. The therapeutic effects, however, are sometimes inconsistent and unpredictable. Human neural crest-derived nasal turbinate stem cells (hNTSCs) are an excellent alternative source of adult stem cells for clinical use because they can be obtained easily by minimally invasive collection procedures and expanded rapidly ex vivo for transplantation. Moreover, the characteristics of hNTSCs, including their proliferation, differentiation, and immunophenotype, are not affected by donor age or passage number (Hwang et al., 2013), while other kinds of stem cells exhibit age and passage-related reduction in multiple characteristics. Method In the present study, we validated the hypothesis that hNTSCs are a clinically promising therapeutic source of adult stem cells for the treatment of Alzheimer’s disease (AD). Here, we evaluated the tprotective effect of hNTSCs against amyloid-b peptide (Ab_1-42) neurotoxic activity in culture of human brain organoid (hBO). hNTSCs were evaluated in comparison with human bone marrow-derived mesenchymal stem cells (hBM-MSCs) according to the effect of transplantation on AD pathology, including PET/CT neuroimaging, immune status, and cognition, in a 5´FAD transgenic mouse model of AD. Results and Discussion Treatment of hBO with Ab_1-42 induced neuronal cell death concomitant with decreased expression of neuronal markers, which was suppressed by hNTSCs cocultured under Ab_1-42 exposure (Lim et al., 2022). Transplantation of hNTSCs greatly reduces the levels of Ab42 and the number of microglia, concomitant with increased survival of hippocampal and cortex neurons when compared with transplantation of hBM-MSCs (Lim et al., 2021). Notably, compared with transplantation of hBM-MSCs, transplantation of hNTSCs significantly enhanced performance on the Morris water maze, with an increased level of TIMP2, which is necessary for spatial memory in young mice and neurons. These results reveal a promising therapeutic effect of hNTSCs and suggest a potential application of hNTSCs of future treatment for patients with AD.