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

BACKGROUND: Impairment 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/ß-catenin signaling cascade in AD-like mouse brain parenchyma. METHODS: The 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 Aß1-42 was injected into lateral ventricles. The AD-like model was confirmed via passive avoidance test and Thioflavin-S staining 21 days following Aß 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/ß-catenin signaling cascade. The spatial learning and memory alternation was evaluated using the Morris water maze (MWM). RESULTS: Data 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 ß-catenin was upregulated and coincided with the suppression of GSK-3ß 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. CONCLUSIONS: The activation of Wnt/ß-catenin pathway via NTF-SCs can be touted as a possible therapeutic approach to restore neurogenesis in AD mice.

Neural Stem Cells Secretome Increased Neurogenesis and Behavioral Performance and the Activation of Wnt/ß-Catenin Signaling Pathway in Mouse Model of Alzheimer's Disease.

Alzheimer's disease is a progressive and age-related neurodegenerative disorder that is manifested by neuropathological changes and clinical symptoms. Recently, cell-based therapeutic interventions have been considered as the promising and effective strategies in this field. Herein, we investigated therapeutic effects of neural stem cell secretome on Alzheimer's disease-like model by triggering of Wnt/ß-catenin signaling pathway. In this study, mice were randomly allocated into three different groups as follows: Control, AD + Vehicle, and AD + NSCs-CM groups. To induce mouse model of AD, Aß1-42 was injected into intracerebroventricular region. Following AD-like confirmation through thioflavin S staining and Passive avoidance test, about 5 µl mouse NSCs-CM was injected into the target areas 21 days after AD induction. For evaluation of endogenous proliferation rate (BrdU/Nestin+ cells), 50 µg/kbW BrdU was intraperitoneally injected for 5 consecutive days. To track NSC differentiation, percent of BrdU/NeuN+ cells were monitored via immunofluorescence staining. Histological Nissl staining was done to neurotoxicity and cell death in AD mice after NSCs-CM injection. Morris Water maze test was performed to assess learning and memory performance. Data showed that NSCs-CM could reverse the learning and memory deficits associated with Aß pathology. The reduced expression of Wnt/ß-catenin-related genes such as PI3K, Akt, MAPK, and ERK in AD mice was increased. Along with these changes, NSCs-CM suppressed overactivity of GSK3ß activity induced by Aß deposition. Besides, NSCs increased BrdU/Nestin+ and BrdU/NeuN+ cells in a paracrine manner, indicating proliferation and neural differentiation of NSCs. Moreover, neurotoxicity rate and cell loss were deceased after NSCs-CM injection. In summary, NSCs can regulate adult neurogenesis through modulating of Wnt/ß-catenin signaling pathway and enhance the behavioral performance in the AD mice. These data present the alternative and effective approach in the management of AD and other cognitive impairments.

Current knowledge and challenges associated with targeted delivery of neurotrophic factors into the central nervous system: focus on available approaches.

During the last decades, numerous basic and clinical studies have been conducted to assess the delivery efficiency of therapeutic agents into the brain and spinal cord parenchyma using several administration routes. Among conventional and in-progress administrative routes, the eligibility of stem cells, viral vectors, and biomaterial systems have been shown in the delivery of NTFs. Despite these manifold advances, the close association between the delivery system and regeneration outcome remains unclear. Herein, we aimed to discuss recent progress in the delivery of these factors and the pros and cons related to each modality.

MicroRNA alterations in neuropathologic cognitive disorders with an emphasis on dementia: Lessons from animal models.

Cognitive dysfunction is a state of losing or having difficulties in remembering, learning, focusing, or making decisions that impact individual healthy life. Small single-stranded and nonprotein coding RNAs, microRNAs (miRNAs) participate actively in regulatory processes, incorporate cognitive signaling pathways, and intensely affect cognitive evolution. miRNAs exert their modification activities through translational or transcriptional processes. Reportedly, cognitive impairment and dementia are rising, especially in developing countries. Herein we provided a brief review of original studies addressing miRNA changes in the most common neurological diseases with a focus on dementia and Alzheimer's disease. It must be noted that an increase in the level of certain miRNAs but a decrease in other ones deteriorate cognitive performance. The current review revealed that induction of miR-214-3p, miR-302, miR-21, miR- 200b/c, miR-207, miR-132, miR-188-3p and 5p, and miR-873 improved cognitive impairment in various cognitive tasks. On the other hand, intentionally lowering the level of miR-34a, miR-124, miR-574, and miR-191a enhanced cognitive function and memory. Synaptic dysfunction is a core cause of cognitive dysfunction; miRNA-34, miRNA-34-c, miRNA-124, miRNA-188-5p, miRNA-210-5p, miRNA-335-3p, and miRNA-134 strongly influence synaptic-related mechanisms. The downregulation of miRNA-132 aggregates both amyloid and tau in tauopathy. Concerning the massive burden of neurological diseases worldwide, the future challenge is the translation of animal model knowledge into the detection of pathophysiological stages of neurocognitive disorders and designing efficient therapeutic strategies. While the delivery procedure of agomir or antagomir miRNAs into the brain is invasive and only applied in animal studies, finding a safe and specific delivery route is a priority.

Human chorionic gonadotropin attenuates amyloid-ß plaques induced by streptozotocin in the rat brain by affecting cytochrome c-ir neuron density.

OBJECTIVES: Amyloid ß plaques, in Alzheimer's disease, are deposits in different areas of the brain such as prefrontal cortex, molecular layer of the cerebellum, and the hippocampal formation. Amyloid ß aggregates lead to the release of cytochrome c and finally neuronal cell death in brain tissue. hCG has critical roles in brain development, neuron differentiation, and function. Therefore, we investigated the effect of hCG on the density of the congophilic Aß plaque and cytochrome c-ir neurons in the hippocampus, prefrontal cortex, and cerebellum of Streptozotocin (STZ)-treated rats. MATERIALS AND METHODS: Alzheimer model in rats (except the control group) was induced by streptozotocin (3 mg/kg, Intracerebroventricularly (ICV)). Experimental group rats received streptozotocin and then different doses of hCG (50, 100, and 200 IU, intraperitoneally) for 3 days. 48 hr after last drug injection and after histological processing, the brain sections were stained by congo red for congophilic amyloid ß plaques and cytochrome c in the hippocampus, prefrontal cortex, and cerebellum were immunohistochemically stained. RESULTS: Density of congophilic Aß plaques and cytochrome c-immunoreactive neurons was significantly higher in ICV STZ treated rats than controls. Treatment with three doses of hCG significantly decreased the density of congophilic Aß plaques and cytochrome c-immunoreactive neurons in the rat hippocampus, prefrontal cortex, and cerebellum in ICV STZ-treated rats (P<0.05). CONCLUSION: hCG can be useful in AD patients to prevent the congophilic Aß plaque formation and decrease cytochrome c-immunoreactive neuron density in the brain.

Human chorionic gonadotropin decreases the phosphorylated tau protein level in streptozotocin-Alzheimeric male rats' hippocampus.

INTRODUCTION: The pharmacological suppression of luteinising hormone or human chorionic gonadotropin (hCG) can reduce Aß plaques in the brains of rats and mice, but the effects of hCG on the phosphorylated tau protein level in the hippocampus have not been studied. Therefore, we investigated the effects of hCG on the phosphorylated tau protein level and its effect on hCG receptor-immunoreactive neuron density in the hippocampus of Alzheimer's disease (AD) model rats (streptozotocin [STZ] injected intracerebroventricularly). MATERIAL AND METHODS: The rats were administered hCG (50, 100, and 200 IU/200 µl saline, intraperitoneally) or vehicle once/day for three days after injection of STZ. The passive avoidance memory test was performed 6 hours after the last hCG injection. The phosphorylated tau protein level in the hippocampus was measured by ELISA, and hCG receptor-immunoreactive neurons were shown by immunohistochemical technique in areas of hippocampus. RESULTS: Treatment with hCG attenuated memory deficiencies and reduced the level of phosphorylated tau protein in the hippocampus. hCG also improved the density of hCG receptor-immunoreactive neurons. The high dose of hCG hormone (200 IU/200 µl saline) seemed to have a significant effect on passive avoidance memory, phosphorylated tau protein concentration, and accumulation of hCG receptor-immunoreactive neurons in Alzheimeric rats' hippocampus. CONCLUSIONS: In conclusion, hCG can provide protection against memory deficits induced by STZ and it can inhibit accumulation of tau hyperphosphorylation in the hippocampus. Furthermore, hCG can increase the hCG receptor-ir neurons number in the rats hippocampus after ICV injection of STZ.