Postdoctoral Fellow Buddhist Tzu Chi General Hospital, Hualien, Taiwan
Abstract: Adipose-derived mesenchymal stem cells (ADSCs) have exhibited promising therapeutic potential in Alzheimer's disease (AD), although the underlying mechanisms remain poorly understood. Previously established Alzheimer's disease neuron model derived from Ts21-induced pluripotent stem cells (Ts21-iPSCs) has been shown to exhibit progressive β-amyloid accumulation during neuronal differentiation. In this study, we employed a Transwell co-culture system to investigate the interaction between neurons derived from Ts21-iPSCs and ADSCs. Our findings revealed that co-culture with ADSCs significantly enhanced the survival rate of AD neurons. Proteomics analysis identified a significant upregulation of LEFTY2 protein in the co-culture medium. Supplementation with 2 nM LEFTY2 markedly improved the survival and growth of AD neurons. Western blot analysis confirmed that LEFTY2 increased the expression of key synaptic proteins, including postsynaptic density protein 95 (PSD-95) and synaptophysin (SYN). Additionally, immunofluorescence staining and Western blot analysis demonstrated that LEFTY2 effectively reduced the expression of β-amyloid 1-42 in AD neurons, potentially through downregulation of apolipoprotein E4 (APOE4). Furthermore, LEFTY2 attenuates phosphorylated tau231 levels and regulates Trem2 and MIF in AD neurons. These results collectively suggest that LEFTY2 not only promotes neuronal growth but also effectively reduces β-amyloid production in AD-iPSC-derived neurons, highlighting its potential as a promising therapeutic candidate for Alzheimer's disease.
