Neurotrophic factor-secreting cells restored endogenous hippocampal neurogenesis through the Wnt/β-catenin signaling pathway in AD model mice

Abstract

AbstractBackgroundImpairment in neurogenesis correlates with memory and  cognitive dysfunction in AD patients. In the recent decade, therapies with stem cell bases are growing and proved to be efficient. This study is a preliminary attempt to explore the impact of NTF-SCs on hippocampal neurogenesis mediated by the Wnt/β-catenin signaling cascade in AD-like mouse brain parenchyma.MethodsThe BALB/c mice were divided into four groups: Control, AD +Vehicle, AD+ TF-SCs-CM and AD+NTF-SCs (n = 10). For AD induction, 100 µM Aβ1-42was injected into lateral ventricles. The AD-like model was confirmed via passive avoidance test and Thioflavin-S staining 21 days following Aβ injection. Next, NTF-SCs were differentiated from ADMSCs, and both NTF-SCs and supernatant (NTF-SCs-CM) were injected into the hippocampus after AD confirmation. Endogenous neural stem cells (NSCs) proliferation capacity was assessed after 50 mg/kbW BrdU injection for 4 days using immunofluorescence (IF) staining. The percent of BrdU/Nestin and BrdU/NeuN positive NSCs were calculated. Real-time RT-PCR was used to detect genes related to the Wnt/β-catenin signaling cascade. The spatial learning and memory alternation was evaluated using the Morris water maze (MWM).ResultsData showed the reduction in escape latency over 5 days in the AD mice compared to the control group. The administration of NTF-SCs and NTF-SCs-CM increased this value compared to the AD-Vehicle group. Both NTF-SCs and NTF-SCs-CM were the potential to reduce the cumulative distance to the platform in AD mice compared to the AD-Vehicle group. The time spent in target quadrants was ameliorated following NTF-SCs and NTF-SCs-CM transplantation followed by an improved MWM performance. IF imaging revealed the increase in BrdU/Nestin+and BrdU/NeuN+in AD mice that received NTF-SCs and NTF-SCs-CM, indicating enhanced neurogenesis. Based on real-time PCR analysis, the expression of PI3K, Akt, MAPK, ERK, Wnt, and β-catenin was upregulated and coincided with the suppression of GSK-3β after injection of NTF-SCs-CM and NTF-SCs. In this study, NTF-SCs had superior effects in AD mice that received NTF-SCs compared to NTF-SCs-CM.ConclusionsThe activation of Wnt/β-catenin pathway via NTF-SCs can be touted as a possible therapeutic approach to restore neurogenesis in AD mice.