ABSTRACT
Alzheimer's disease (AD) is a common neurodegenerative disease that is always accompanied by synaptic loss in the brain. Safflower yellow (SY) is the extract of safflower, a traditional Chinese medicine, which has shown neuroprotective effects in recent studies. However, the mechanism of SY in protecting synapses remains unclear. In this study, we are going to study the mechanism of how SY treats AD in terms of synaptic plasticity. We found, via behavioral experiments, that SY treatment could improve the abilities of learning and memory in APP/PS1 mice. In addition, using Golgi staining and HE staining, we found that SY treatment could reduce the loss of dendritic spines in the pathological condition and could maintain the normal physiological state of the cells in cortex and in hippocampus. In addition, the results of immunofluorescence staining and western blotting showed that SY treatment could significantly increase the expression of synapse-related proteins. Moreover, after being treated with SY, the expression of iNOS (marker of M1 microglia) declined remarkably, and the level of Arginase-1 (marker of M2 microglia) increased significantly. Finally, we found BDNF/TrkB/ERK signaling cascade was activated. These results indicate that SY enhances synaptic plasticity in APP/PS1 mice by regulating microglia activation phenotypes and BDNF/TrkB/ERK signaling pathway.
Subject(s)
Alzheimer Disease/drug therapy , Brain-Derived Neurotrophic Factor/physiology , Chalcone/analogs & derivatives , Drugs, Chinese Herbal/therapeutic use , MAP Kinase Signaling System/drug effects , Membrane Glycoproteins/physiology , Microglia/drug effects , Neuronal Plasticity/drug effects , Phytotherapy , Protein-Tyrosine Kinases/physiology , Alzheimer Disease/genetics , Amyloid beta-Protein Precursor/genetics , Animals , Arginase/biosynthesis , Arginase/genetics , Cerebral Cortex/chemistry , Cerebral Cortex/drug effects , Cerebral Cortex/pathology , Chalcone/therapeutic use , Dendritic Spines/drug effects , Dendritic Spines/ultrastructure , Disease Models, Animal , Donepezil/pharmacology , Donepezil/therapeutic use , Enzyme Induction/drug effects , Escape Reaction/drug effects , Female , Hippocampus/chemistry , Hippocampus/drug effects , Hippocampus/pathology , Male , Memory, Long-Term/drug effects , Memory, Short-Term/drug effects , Mice , Mice, Inbred C57BL , Mice, Transgenic , Microglia/physiology , Morris Water Maze Test/drug effects , Nerve Tissue Proteins/biosynthesis , Nerve Tissue Proteins/genetics , Neuronal Plasticity/physiology , Nitric Oxide Synthase Type II/biosynthesis , Nitric Oxide Synthase Type II/genetics , Presenilin-1/genetics , Random AllocationABSTRACT
Geniposidic acid (GPA) is an extract from Eucommia ulmoides Oliv. Bark (Eucommiaceae). Accumulating evidences have reported GPA has anti-aging, anti-oxidative stress, anti-inflammatory and neurotrophic effects on neurons. However, whether GPA could alleviate memory deficits in Alzheimer's disease animal models is not clear. We aimed to investigate the effect of GPA treatment on cognitive performance, Aß deposition and glial cells activation in the transgenic mouse model of AD. 6-7 months APP/PS1 mice were given GPA for 90 days; behavioral experiments were executed to estimate the memory and spatial learning abilities of mice, and the mechanism of neuroprotective effect of GPA was investigated with a focus on amyloid-ß deposition, astrocytes and microglia activation and neuroinflammation. GPA treatment significantly improved the spatial learning and memory abilities and also decreased cerebral amyloid-ß deposition in APP/PS1 mice. Via HE staining, we found that GPA could ameliorate histopathological changes in cerebrum. We also found that GPA treatment inhibited the activation of astrocytes and microglia, down-regulated the expression of pro-inflammatory cytokines and iNOS, and up-regulated the expression of anti-inflammatory cytokines and Arg-1. In addition, GPA down-regulated the gene expression of HMGB-1 receptors (TLR2, TLR4 and RAGE) then mediated MyD88, TRAF6 and phospho-ERK1/2, subsequently modulated the expression of key AP-1 and NF-κB family members (c-Fos, c-Jun and p65). The reversal of the pro-inflammatory state suggested GPA can serves as a multi-target candidate by alleviating Aß deposition and neuroinflammation for the auxiliary therapy of Alzheimer's disease.
Subject(s)
Alzheimer Disease/drug therapy , Anti-Inflammatory Agents/therapeutic use , Iridoid Glucosides/therapeutic use , Memory Disorders/drug therapy , Neuroprotective Agents/therapeutic use , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Animals , Anti-Inflammatory Agents/pharmacology , Astrocytes/drug effects , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Cytokines/metabolism , Disease Models, Animal , Down-Regulation , Hippocampus/drug effects , Hippocampus/metabolism , Iridoid Glucosides/pharmacology , Memory/drug effects , Memory Disorders/genetics , Memory Disorders/metabolism , Mice, Transgenic , Microglia/drug effects , Neuroprotective Agents/pharmacology , Presenilin-1/genetics , Signal Transduction/drug effects , Spatial Learning/drug effects , Toll-Like Receptor 2/genetics , Toll-Like Receptor 4/geneticsABSTRACT
Safflower yellow (SY) is an aqueous extract of natural safflower. Our laboratory has reported protective effects of alleviating memory impairment with SY in a transgentic mouse model of Alzheimer's disease. The possible beneficial effects of SY on amyloid-ß-induced neuroinflammation in dementia remain unclarified. This study we hypothesize that astrocytes and microglia may cause amyloid-ß deposition and produce a neuroinflammatory response, aims to explain the role and mechanism of SY in regulating glial activation and reducing Aß deposition in Aß1-42 induced rat model. Wistar rats were treated with SY for one month after bilateral hippocampal injection of aggregated Aß1-42; behavioral tests were performed to demonstrate the amelioration of cognitive function. After that, the contents of iNOS, IL-1ß, IL-6, and TNF-α in AD brain was detected. Western blot and real-time PCR were used to detect the M1 and M2-associated markers to demonstrate the activation of microglia. The conducted experiments have revealed that SY could strengthen spatial learning and memory ability of dementia rats, decrease the contents of iNOS, IL-1ß, IL-6, and TNF-α and depress the activation of glial cells. Moreover, the SY treatment inhibited the M1 release of pro-inflammatory cytokines (iNOS and CD86), increased the expression of arginase-1, CD206, and YM-1 thereby reduced inflammation in model rats. Thus our results indicated that SY has very important theoretical and clinical value for the research and development of Chinese medicine for the treatment of AD.
