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1.
AIM: To explore the therapeutic effect of a novel Rho kinase inhibitor FSD-C10 on β-amyloid protein precursor (APP)/presenilin-1 (PS1) double transgenic mice. METHODS: The transgenic mice overexpressing human APP with the Swedish mutation (695) and human PS1 with ΔE9 mutation at the age of 8 months were used in this study. The mice were randomly divided into model group and FSD-C10 intervention group, and wild-type mice at the same age served as normal controls. The mice in FSD-C10 intervention group were treated with FSD-C10 (25 mg·kg-1·d-1) for 2 months by intraperitoneal injection. The mice in model group and the wild-type mice were injected with saline in the similar manner. Morris water maze (MWM) test was applied to examine the capacity of learning and memory. The Aβ1-42 deposition, Tau protein phosphorylation, and the expression of β-site APP-cleaving enzyme (BACE) as well as inflammatory molecules, such as TLR-4 and NF-κB, and M1/M2 microglial markers, such as iNOS and Arg-1, were determined by the methods of immunohistochemistry and Western blot. RESULTS: Compared with model group, FSD-C10 significantly improved the learning and memory abilities of APP/PS1 double transgenic mice, accompanied by reduced Aβ1-42 deposition, Tau protein phosphorylation and BACE expression in the hippocampus. The intervention of FSD-C10 decreased the protein levels of TLR-4 and p-NF-κB, reduced the expression of iNOS and increased the expression of Arg-1 in the brain tissues. CONCLUSION: The novel Rho kinase inhibitor FSD-C10 improves the capacity of spatial learning and memory in APP/PS1 double transgenic mice, which may be related to the inhibition of TLRs/NF-κB signaling pathway, the reduction of the secretion of inflammatory molecules and the polarization of anti-inflammatory M2 microglia, thus improving the inflammatory microenvironment of the brain in APP/PS1 double transgenic mice.  相似文献   

2.
AIM:To observe the effects of Rho kinase inhibitor fasudil on promoting nerve regeneration and improving cognitive function in amyloid precursor protein/presenilin 1 double transgenic (APP/PS1 Tg) mice, a widely used model of Alzheimer disease. METHODS:Male APP/PS1 Tg mice at 8 months old were randomly divided into 2 groups:the mice in fasudil group were intraperitoneally injected with fasudil at 25 mg/kg, while the mice in NS group were intraperitoneally injected with normal saline (NS), once daily for 2 months. Age-and sex-matched wild-type (WT) mice without treatment were used as controls. The Morris water maze (MWM) test and SMART 3.0 behavioral record system were applied to examine and analyze the spatial cognitive function of the mice. The protein levels and distribution of p-Tau, ChAT, BrdU and nestin in the hippocampal dentate gyrus (DG) and CA3 area and cerebral cortex were detected by immunohistochemistry. The protein levels of p-APP(Thr668) and p-Tau in the brain were analyzed by Western blot. RESULTS:Compared with control group, the APP/PS1 Tg mice (10 months old at the time of testing) treated with NS displayed the increase in the latency to target, and the decreases in the time and distance in SW (%) during the MWM test (SW was located in the area of the platform), indicating impaired cognition, which was reversed by fasudil treatment, indicating that the cognitive function was improved in the APP/PS1 Tg mice. In addition, compared with NS group, fasudil treatment significantly reduced the protein level of p-Tau, and increased the protein level of p-APP in the central nervous system (CNS) and the number of cholinergic neurons in the hippocampus. The neuronal axon regeneration in the hippocampus was promoted, and the endogenous neural stem cell proliferation in subgranular zone and subventricular zone of the hippocampal DG was also mobilized. CONCLUSION:Fasudil reverses spatial cognitive dysfunction in APP/PS1 Tg mice through decreasing the protein level of p-Tau, increasing the level of soluble APP, promoting the regeneration of cholinergic neurons, and mobilizating the endogenous neural stem cell proliferation in the CNS.  相似文献   

3.
AIM:To explore the neuroprotective effects of hyperbaric oxygen (HBO) therapy on the brain of APP/PS1 transgenic (TG) mice. METHODS:Four-month-old APP/PS1 transgenic mice and the wild-type (WT) littermates were randomly divided into 3 groups:TG+HBO, TG, and WT. All mice were administrated with HBO or control treatment for 6 cycles. The animals were subjected to Morris water maze. The mice were killed and the brains were collec-ted for coronal section and other biochemical analysis. The brain sections were subjected to immunofluorescence staining for observing the amyloid plaques. The levels of Aβ40 and Aβ42 were measured by ELISA. The protein levels of Sirt1, BACE1, APP, α/β-CTF and synaptophysin were determined by Western blot. RESULTS:In TG+HBO group, HBO treatment reduced Aβ generation and plaque formation in the brains as compared with TG group (P<0.01). HBO treatment also increased the protein level of Sirt1, but reduced the protein level of BACE1 and the cleavage of APP by BACE1 (P<0.01). HBO treatment attenuated the loss of spines and synapses, thus rescuing the learning and memory deficits in APP/PS1 mice. CONCLUSION:HBO treatment rescues cognitive deficits of APP/PS1 transgenic mice by increasing the level of Sirt1 and reducing the level of BACE1 protein, thus reducing the generation of Aβ and its neurotoxicity in APP/PS1 transgenic mice.  相似文献   

4.
AIM: To investigate the effect of bone marrow mesenchymal stem cell (BMSC) transplantation on learning and memory abilities and pathological changes of Alzheimer disease (AD) mice and the molecular mechanisms. METHODS: C57/BL6 wild-type (WT) and transgenic (Tg) mice were randomly divided into 4 groups:WT/PBS group, WT/BMSCs group, Tg/PBS group and Tg/BMSCs group. The mice were administered with PBS or BMSCs via intracerebroventricular injection. Spatial learning and memory abilities of the mice were evaluated by Morris water maze test on the 3rd day after surgery. Real-time PCR was applied to detect the mRNA expression of CX3C chemokine ligand 1 (CX3CL1), CX3C chemokine receptor 1 (CX3CR1), IL-1β, TNF-α, Nurr1, YM1, insulin-degrading enzyme (IDE) and matrix metalloproteinase 9 (MMP9). The protein levels of CX3CL1 and Aβ42 were measured by ELISA. Western blot was used to detect the protein expression of postsynaptic density protein 95 (PSD95) and synaptophysin (SYP). RESULTS: The transplanted BMSCs were observed near the hippocampus of APP/PS1 mice on the 10th postoperative day. The escape latency of the mice in Tg/PBS group was significantly longer than that in the WT/PBS mice (P<0.05). Compared with Tg/PBS group, the escape latency of Tg/BMSCs group was significantly shorter (P<0.05), and the mRNA and protein levels of CX3CL1 in Tg/BMSCs group were significantly higher than those in Tg/PBS group (P<0.01). The results of immunohistofluorescence staining showed that BMSC transplantation promoted the activation of microglia in the brain of WT and Tg mice. The mRNA expression of YM1 was up-regulated in WT/BMSCs group and Tg/BMSCs group (P<0.05). Compared with WT/PBS mice, the mRNA expression of TNF-α in the cortex and hippocampus of Tg/PBS group was significantly increased (P<0.05), and the mRNA expression of Nurr1 in the cortex was significantly decreased (P<0.01). Meanwhile, the mRNA expression of TNF-α in the cortex of Tg/BMSCs mice was decreased (P<0.01) and the mRNA expression of CX3CR1 and Nurr1 was up-regulated compared with Tg/PBS group (P<0.05). The results of Western blot showed that the protein levels of PSD95, p85, p110 and p-Akt in Tg/BMSCs group were significantly higher than those in Tg/PBS group (P<0.05). Finally, BMSC transplantation reduced the protein level of Aβ42 in APP/PS1 mice (P<0.05), and increased the mRNA expression of IDE and MMP9 in the hippocampus (P<0.05). CONCLUSION: BMSC transplantation modulates neuroinflammatory responses and promotes neuroprotective factor and synaptic protein expression, thus improving the learning and memory abilities in the APP/PS1 mice, which may be achieved by up-regulating the expression of CX3CL1.  相似文献   

5.
AIM: To investigate the protective effects of astrocyte protein phosphatase 2A(PP2A) up-regulation on APP/PS1 double transgenic mice.METHODS: An eGFP-wtPP2A lentivirus with glial fiber acidic protein promoter was constructed to specifically increase PP2A expression in the astrocytes. The mice were divided into wild -type mice+vector virus group(Con), APP/PS1 transgenic mice+vector virus group(APP/PS1) and APP/PS1 transgenic mice+eGFP-wtPP2A lentivirus group(PP2A) by lateral ventricular injection of the lentivirus. Four weeks after injection of the virus, the immunofluorescence of brain slices were used to detect the level of β-amyloid protein(Aβ). Golgi staining was used to detect the changes of dendritic spine density and morphology. Electron microscopy was applied to detect the thickness of postsynaptic density(PSD). The Morris water maze test was applied to examine the learning and memory abilities of the mice.RESULTS: Up-regulation of PP2A in the astrocytes attenuated Aβ level increasing in APP/PS1 group. Up-regulation of PP2A in the astrocytes significantly attenuated both decreases in the dendritic spine density and the percentage of mushroom-like dendritic spines in the hippocampal CA3 region of APP/PS1 mice. Up-regulation of PP2A in the astrocytes significantly attenuated the reduced thickness of PSD in APP/PS1 group. Up-regulation of PP2A in the astrocytes attenuated the escape latency extending in APP/PS1 group.CONCLUSION: Up-regulation of PP2A in the astrocytes reduces AD-like pathological changes, and attenuates synaptic impairment, synaptic plasticity deficits and cognitive impairment in the APP/PS1 double transgenic mice.  相似文献   

6.
AIM: To explore the protective effect of osthole on the SH-SY5Y cells transfected with APP595/596 gene, and to investigate the molecular mechanism. METHODS: The SH-SY5Y cells were transfected with APP595/596 gene in vitro for establishing a cell model to study the pathogenic role of amyloid β-protein (Aβ). The cell viability was detected by CCK-8 assay. The release of lactate dehydrogenase (LDH) was determined by the colour reaction of diaphorase-INT. The cell apoptotic rate was analyzed by flow cytometry. The expression of β-site APP cleaving enzyme 1(BACE1) at mRNA and protein levels was detected by RT-PCR and Western blot. The expression of Aβ was measured by the technique of immunofluorescence cytochemistry and Western blot. RESULTS: Treatment with osthole inhibited the LDH release, and increased the viability of the cells. The percentage of apoptotic cells was also significantly decreased. Osthole also inhibited the expression of BACE1 at mRNA and protein levels and the protein expression of Aβ. CONCLUSION: Osthole has protective effect on SH-SY5Y cells transfected with APP595/596 gene. The mechanism may be association with inhibiting the mRNA and protein expression of BACE1.  相似文献   

7.
AIM: To investigate the expression changes of brain-derived neurotrophic factor (BDNF) in the cerebral cortex and hippocampus and their effects on the ability of learning and memory in the wild-type (WT) mice and APP/PS1 transgenic mice. METHODS: WT mice and APP/PS1 transgenic mice were selected as study subjects. Aβ plaques, apoptosis rate and BDNF expression in the cerebral cortex and hippocampus of WT mice and APP/PS1 transgenic mice were detected by the methods of Congo red staining, TUNEL, immunofluorescence and Western blot. The abilities of learning and memory were determined by Morris water maze test. RESULTS: The Aβ plaques appeared in the cerebral cortex and hippocampus of APP/PS1 transgenic mice, and the number of Aβ plaques in 12-month-old mice was larger than that in 6-month-old mice (P<0.05). The number of apoptotic neurons in the cerebral cortex and hippocampus of 12-month-old APP/PS1 transgenic mice was larger than that of WT mice (P<0.01). The expression level of BDNF in the cerebral cortex and hippocampus of WT mice was higher than that of APP/PS1 transgenic mice (P<0.01). The Morris water maze test showed that the escape latency in APP/PS1 transgenic mice was longer than that in WT mice, and the times across the platform quadrant in 60 s was less than that in WT mice (P<0.01). The swim-tracking path of APP/PS1 transgenic mice was disordered and irregular. CONCLUSION: The expression of BDNF in the cerebral cortex and hippocampus of APP/PS1 transgenic mice was lower than that of WT mice, accompanied by increased neuronal apoptosis and decreased spatial learning and memory ability. The decrease in learning and memory ability may be related to decreased BDNF expression in the cerebral cortex and hippocampus of APP/PS1 transgenic mice, leading to increased neuronal apoptosis, which may be one of the pathological mechanisms of Alzheimer disease.  相似文献   

8.
AIM:To explore the effect of TAK-242 on the learning and memory ability of C57BL/6 mice with sepsis-associated encephalopathy induced by lipopolysaccharide (LPS), to observe the pathological and morphological changes of the mouse brain, and to explore the mechanism of protein pathway associated with the effect of TAK-242. METHODS:Healthy female C57BL/6 mice (n=80), aged 10~12 months, weighing 20~30 g, were randomly divided into 4 groups (n=20):blank control (CON) group, TAK-242 control (TAK) group, sepsis encephalopathy model (LPS) group and TAK-242 pretreatment (T+L) group. Peripheral inflammation in the mice was detected by testing the arterial blood and lung tissues. The behavioral changes of the mice were observed by the open-field test, elevated plus-maze test (EPMT) and Morris water maze test. Immunohistochemistry was performed to observe the changes of microglia-specific marker, ionized calcium-binding adapter molecule-1 (Iba-1), in the hippocampus. Finally, the protein expression levels of NF-κB p65, TLR4, Aβ1-42 and p-tau (S396) were determined by Western blot. RESULTS:Compared with CON group, the mice in other groups didn't showed significant difference in the arterial blood gas analysis and lung tissue HE staining. In the anxiety and fear behavior tests, central active duration and times of crossing central field of the mice in LPS group were significantly decreased compared with CON group (P<0.01). The times of open arm entry and the times of head area entry in the EPMT were significantly less than those in CON group (P<0.05). The escape latency of spatial probe experiments was significantly extended (P<0.05). Microglial activation in the hippocampus was significantly increased (P<0.05) and the protein expression levels of NF-κB p65, TLR4, Aβ1-42 and p-tau (S396) were significantly increased (P<0.01). Conversely, compared with LPS group, the central active duration and times of crossing central field in T+L group were significantly increased (P<0.01). The times of open arm entry and the times of head area entry in the EPMT were significantly increased (P<0.05). The escape latency of spatial probe experiments was significantly shortened (P<0.05). Microglial activation in the hippocampus was significantly decreased and the protein expression levels of NF-κB p65, TLR4, Aβ1-42 and p-tau (S396) were down-regulated (P<0.05). CONCLUSION:TAK-242 obviously improves the ability of learning and memory, and the mechanism may be related to the inhibition of the central microglia activation and down-regulation of protein expression levels of NF-κB p65, TLR4, Aβ1-42 and p-tau (S396).  相似文献   

9.
AIM:To investigate the effect of tenuigenin(TEN) on hyperphosphorylation of tau protein in neurons of amyloid β-peptide1-40(Aβ1-40) -induced Alzheimer disease(AD) rats. METHODS:Aβ1-40 was injected into hippocampus CA1 region of the rats to establish AD model. TEN at different doses(18.5 mg/kg, 37.0 mg/kg and 74.0 mg/kg) was intragastrically administered. The protein expression of protein kinase A(PKA),protein phosphatase 2A(PP2A), total tau and p-tau(Ser396) in the neurons was observed by the method of immunohistochemistry. The protein content of total tau and p-tau(Ser396), and the expression level of PKA and PP-2A were detected by Western blotting analysis. RESULTS:In Aβ1-40 group, the level of total tau, the phosphorylation of tau protein and the expression of PKA were significantly increased compared with those in sham operation group. Meanwhile, the expression of PP2A in Aβ1-40 group was lower than that in sham operation group. In TEN treatment group, the level of total tau, the phosphorylation of tau protein and the expression of PKA were markedly decreased, and the expression of PP2A was increased as compared with Aβ1-40 group. CONCLUSION:TEN may protect the neurons from the toxic effect of Aβ1-40 and reduce the hyperphosphorylation of tau(Ser396) in the neurons of AD rats by activating the expression of PP2A and inhibiting the expression of PKA.  相似文献   

10.
AIM：To estimate the neural differentiation efficiency of bone marrow mesenchymal stem cells (MSCs) derived from amyloid precursor protein (APP) transgenic mice and to investigate the correlation with Notch1 signaling and the autophagy activity during the differentiation. METHODS：The MSCs were divided into APP group (MSCs from APP transgenic mice) and WT group (MSCs from wild-type mice). MSCs were treated with β-mercaptoethanol as an inducer for differentiating into neurons. The levels of Aβ40 and Aβ42 were measured using enzyme-linked immunosorbent assay kits. The expression of neural cell-specific markers, neuron-specific enolase (NSE) and microtubule-associated protein 2 (MAP-2), was measured by immunocytochemistry and Western blotting. The expression levels of Notch1, Notch intracellular domain (NICD), Hes5, LC3 and p62 (a selective substrate of autophagy) were also detected by Western blotting. RESULTS：The neural differentiation capacity and the Aβ expression level of the MSCs in APP group were higher than those in WT group, and stronger inhibition of Notch1 signaling pathway in the MSCs from APP group was observed. However, the process of autophagy, which is essential for the survival and function of the neural cells, was impaired in the neural differentiated counterpart of the MSCs in APP group. CONCLUSION:Over-expression of APP might contribute to the high neural differentiation capacity of MSCs by inhibiting Notch1 signaling pathway in vitro. However, autophagy is impaired in the differentiated MSCs from APP transgenic mice.  相似文献   

11.
AIM: To investigate the therapeutic and preventive effects of paeoniflorin (PF) on APP/PS1 mice, and to explore the possible mechanism. METHODS: Fifteen male 5-month-old APP/PS1 non-dominant mice were chosen as normal control group, 15 male 5-month-old APP/PS1 double transgenic mice were used as model group, and 15 male 5-month-old APP/PS1 double transgenic mice treated with 5 mg/kg PF by intraperitoneal injection were allocated in administation group. The learning and memory ability of the mice in each group was detected by Morris water maze. The apoptosis was assessed by TUNEL fluorescence staining. The protein expression of PI3K, Akt, p-PI3K, p-Akt, caspase-3, caspase-9, Bcl-2 and Bax in cerebral cortex and hippocampus was detected by Western Blot. The protein expression levels and distribution of caspase-3 and caspase-9 were detected by immunohistochemistry. RESULTS: (1) Compared with normal control group, the learning and memory ability declined in APP/PS1 model group. Compared with APP/PS1 model group, PF obviously improve the ability of learning and memory in mice. (2) Compared with normal control group, the apoptosis of nerve cells in APP/PS1 model group significantly increased and distributed in wider areas, while that in PF group was reduced (P<0.05). (3) Compared with APP/PS1 model group, PF could significantly lower pro-apoptotic factors, caspase-3, caspase-9 and Bax (P<0.05), and increase the expression of anti-apoptotic factors, p-PI3K, p-Akt and Bcl-2 (P<0.05). CONCLUSION: PF can up-regulate the expression of Bcl-2 and down-regulate the expression levels of caspase-9, caspase-3 and Bax via the activation of PI3K/Akt pathway, thereby inhibiting the nerve cell apoptosis and protecting the nerve cells, so as to treat neurodegenerative diseases.  相似文献   

12.
AIM: To observe the effects of neuroglobin(NGB) overexpression on the apoptosis induced by Aβ in the brains of double transgenic AD(APPswe/PS1dE9) mice and to explore its potential mechanisms.METHODS: Twenty-four 13-month-old double transgenic AD mice were randomly divided into 3 groups:intracerebroventricular injection with normal saline(NS) group, intracerebroventricular injection with pcDNA3.1 and NS group, and intracerebroventricular injection with pcDNA3.1 and pNGB group. Immunohistochemistry was used to detect the expression of Aβ1-42 in the brains. TUNEL staining was used for analyzing the apoptosis, and the protein levels of cleaved caspase-3, caspase-9, PI3K, Akt and p-Akt were determined by Western blot.RESULTS: After intracerebroventricular injection with pNGB, the areas of Aβ1-42 in the hippocampus and cortex were decreased compared with NS group and pcDNA3.1+NS group(P<0.01). The TUNEL-positive staining cells in the pNGB group were less than those in NS group and pcDNA3.1 group(P<0.01). NGB overexpression attenuated the protein levels of cleaved caspase-3 and caspase-9(P<0.01), but induced the production of PI3K and p-Akt(P<0.01).CONCLUSION: Overexpression of pNGB significantly inhibits the generation of Aβ and attenuates the apoptosis induced by Aβ, indicating that NGB overexpression activates PI3K/Akt pathway and inhibits the production of cleaved caspase-3 and caspase-9, which were tightly related with apoptosis.  相似文献   

13.
AIM: To investigate the expression of α-synuclein in the brain of AD-like animal model at different age and to explore the pathology mechanism of α-synuclein in neural degeneration.METHODS: APP V717I transgenic (Tg) mouse model of Alzheimers disease was observed at age of 4,10 and 16 months.The Tg mice were randomly divided into 3 model groups (4,10 and 16 months of age).Control adopted the same age and background C57BL/6J mice.The mRNA expression of α-synuclein was measured by genechips and RT-PCR method.The protein of α-synuclein was detected by immuno-histochemistry and Western blotting.RESULTS: The expression of α-synuclein mRNA increased significantly in hippocampus and cortex in Tg mice at age of 4 months,10 months and 16 months compared with age matched controls.The production of α-synuclein protein also increased significantly in hippocampus and cortex in Tg mice at 3 groups.With aging,α-synuclein expression was increased and aggregated in Tg mice.CONCLUSION: Overexpression and aggregation of α-synuclein in different age of APP transgenic mice may play a key role in learning-memory deficit and the pathology of Alzheimers disease,aging,and neural degeneration.  相似文献   

14.
AIM: To observe the influences of different concentrations of MG132 on apoptosis and beta-amyloid protein(Aβ) generation in SH-SY5Y cells, and to explore the underlying mechanism.METHODS: SHSY-5Y cells were incubated with MG132 for 24 h. The final concentrations of MG132 were 2.5, 5 and 10 μmol/L. The cell viability was determined by MTT assay. The cell apoptosis was assessed by flow cytometry. The levels of Aβ were measured by ELISA. The relative protein levels were detected by Western blot.RESULTS: In the SH-SY5Y cells, MG132 reduced the cell viability, induced the cell apoptosis, increased the level of Aβ, and increased the expression of the related proteins for Aβ generation in a concentration-dependent manner.CONCLUSION: MG132 induces apoptosis and increases the levels of Aβ1-42 and Aβ1-40 by regulating the proteins related to Aβ generation in the SH-SY5Y cells.  相似文献   

15.
WANG Feng  HAN Bai  HAN De-wu 《园艺学报》2009,25(5):924-928
AIM: The objective of the study was to explore whether intestinal endotoxemia participate in the development of Alzheimer disease. METHODS: Adult Wistar rats were subjected to 90 days intraperitoneal injection with D-galactose and aluminum trichloride (AlCl3) to establish the model of Alzheimer disease. After the administration, the study and memory ability in the rats were observed by Morris water maze. The level of lipopolysaccharide (LPS) in the sera of Alzheimer diseases rats was determined by tachypleus amebocyte lysate method. The level of tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) in the sera were determined by radioimmunoassay. The expressions of amyloid β-protein precursor (APP), presenilin 1 (PS1) and β-site APP-cleaving enzyme (BACE) in hippocampus were detected by RT-PCR. RESULTS: Compared with the normal control, the level of LPS in the sera and the expressions of APP, PSI, BACE mRNA in the hippocampus were markedly increased (P<0.01). CONCLUSION: The rat model of Alzheimer disease established by D-galactose and AlCl3 exposure is accompanied intestinal endotoxemia. This result suggests that intestinal endotoxemia plays an important role in the development of Alzheimer disease.  相似文献   

16.
AIM：To explore the anti-inflammatory effect of huperzine A (HupA) and its neuroprotective effect on rat neural stem cells (NSCs). METHODS：The microglia and NSCs were isolated from neonatal rat hippocampal tissues and co-cultured in a Transwell system. The cells were divided into 3 groups：control group, amyloid beta-peptide (Aβ) group and HupA group. The microglia layer in Aβ group was treated with Aβ1-42 (10 μmol/L), while that in HupA group was pretreated with HupA (1 μmol/L) before Aβ1-42 stimulation. The culture supernatant levels of inflammatory mediators, including interleukin 6 (IL-6), tumor necrosis factor α (TNF-α) and macrophage inflammatory protein 1α (MIP-1α), were detected by LiquiChip technique. The apoptosis of NSCs was determined by flow cytometry and Western blotting. RESULTS：The microglia secreted a large number of inflammatory mediators with the stimulation of Aβ. In Aβ group, the levels of IL-6, TNF-α and MIP-1α were significantly higher than those in control group at 72 h (P<0.01), and the apoptotic rate of NSCs was 25.46% (P<0.01). In HupA group, the concentrations of IL-6, TNF-α and MIP-1α decreased significantly as compared with Aβ group (P<0.01), and the apoptotic rate of NSCs was only 8.05% (P<0.01). The Bcl-2/Bax ratio in HupA group was higher than that in Aβ group (P<0.05). CONCLUSION：Huperzine A reduces the secretion of cytokines and chemokines, and attenuates microglia-mediated neuroinflammation, thus protecting NSCs against inflammation-induced apoptosis.  相似文献   

17.
AIM: To investigate the effect of high mobility group box-1 protein (HMGB1) on the expression of nuclear factor-κB (NF-κB) in BV-2 cells stimulated with amyloid β-protein (Aβ)25-35. METHODS: Cultured BV-2 cells in logarithmic growth phase were divided into 4 groups:normal cell group (without any treatment), model group (treated with Aβ25-35 at 40 μmol/L), RNA interference (RNAi) group (conducted with HMGB1-siRNA followed by Aβ25-35 stimulation) and solvent control group (treated with 0.1% DMSO). After treatment with Aβ25-35 for 24 h, the protein levels of HMGB1 and NF-κB in BV-2 cells were determined by Western blot. RESULTS: Aβ25-35 at 40 μmol/L was used to stimulate BV-2 cells. The GFP fluorescence-tagged HMGB1-siRNA (30 nmol/L) was used to transfect BV-2 cells and its transfection efficiency was about 80%~90%. The results of Western blot showed that the protein level of HMGB1 was significantly decreased after the interference of siRNA fragment (P<0.05). The protein levels of HMGB1 and nucleic NF-κB p65 were dramatically increased in BV-2 cells stimulated with Aβ25-35 (P<0.05). After RNA interference with HMGB1, the expression of HMGB1 and nucleic NF-κB p65 were significantly decreased in BV-2 cells stimulated with Aβ25-35 (P<0.05). CONCLUSION: RNA interference with HMGB1 reduces the expression of nucleic NF-κB in BV-2 cells stimulated with Aβ25-35.  相似文献   

18.
AIM:To observe the effect of rapamycin (Rapa) on the circadian rhythm disorder in C57BL/6 mice and the abnormal expression of Per2 in mouse hippocampal neuronal cell line HT22 induced by amyloid β-protein 31-35 (Aβ31-35).METHODS:The 6~8-week-old male C57BL/6 mice were selected for wheel-running behavior experiment. The effect of Rapa on the circadian rhythm disorder induced by Aβ31-35 was analyzed. The HT22 cells were randomly divided into control group, Aβ31-35 group, Rapa+Aβ31-35 group and Rapa group. The cell viability was measured by CCK-8 assay. Real-time PCR was used to detect the mRNA expression of Per2, and Western blot was applied to examine the expression of Per2 protein at circadian time (CT) 16. RESULTS:Compared with control group, Aβ31-35 disturbed the circadian rhythm which exhibited significantly longer free running period. However, the disruption was significantly relieved by pretreatment with Rapa compared with Aβ31-35 treatment, which manifested significantly decreased free running period (P<0.05). Aβ31-35 decreased the viability of HT22 cells compared with control group, and Rapa pretreatment reduced the toxicity of Aβ31-35 through up-regulating the cell viability. Abnormal mRNA expressions of Per2 was induced by Aβ31-35 in the HT22 cells. Rapa pretreatment reversed the abnormal expression of Per2 at mRNA level induced by Aβ31-35. Aβ31-35 significantly decreased the protein expression of Per2 at CT16. Pretreatment with Rapa significantly improved the protein expression of Per2. CONCLUSION:Rapa attenuates the circadian rhythm disorder induced by Aβ31-35 in C57BL/6 mice, and improves the abnormal expression of Per2 induced by Aβ31-35 in HT22 cells.  相似文献   

19.
YANG Yi  TANG Xiao-li  LIU Yue  FANG Fang 《园艺学报》2019,35(11):2028-2034
AIM: To explore whether the damage of neurons induced by amyloid β-protein (Aβ) is related to the regulation of autophagy and its mechanism based on Akt/mTOR pathway. METHODS: SH-SY5Y cells were incubated with Aβ25-35 (5 μmol/L, 10 μmol/L, 15 μmol/L, 20 μmol/L and 25 μmol/L) for 24 h, and the cell viability was measured by MTT assay. The protein levels of LC3-I, LC3-II, Akt, p-Akt, mTOR and p-mTOR in the SH-SY5Y cells were determined by Western blot. After the SH-5Y5Y cells were incubated with autophagy inducer rapamycin (Rapa) or autophagy inhibitor 3-methyladenine (3-MA) combined with Aβ25-35 for 24 h, the cell viability and related protein expression were detected by the same methods above mentioned. RESULTS: Each concentration of Aβ25-35 damaged SH-SY5Y cells and decreased the viability of SH-SY5Y cells. Aβ25-35 increased the expression of autophagy marker protein LC3-II, increased the level of LC3-II/LC3-I, and down-regulated the phosphorylation level of Akt and mTOR proteins (P<0.05). When combined with autophagy inducer Rapa, the cell viability was not significantly affected, the expression of LC3-II protein was increased, LC3-II/LC3-I was increased significantly, and p-mTOR/mTOR level was decreased (P<0.05). When combined with autophagy inhibitor 3-MA, the protein expression of LC3-II and the level of LC3-II/LC3-I showed a downward trend, while the level of p-Akt/Akt was decreased (P<0.05). CONCLUSION: Aβ25-35 may induce SH-SY5Y cell autophagy and injury by down-regulating phosphorylation levels of Akt and mTOR proteins.  相似文献   

20.
AIM: To investigate whether chrysophanol alleviates amyloid β-protein (Aβ)-induced cognitive dysfunction and the underlying antioxidative mechanism.METHODS:Adult male Wistar rats (230~250 g) were randomly divided into control group, Aβ1-42 group, chrysophanol group, and Aβ1-42+chrysophanol (1, 10 and 100 mg/kg) groups. Aβ1-42 was delivered by intracerebroventricular injection under the guidence of a brain stereotaxic apparatus. Y-maze test, open-field test and Morris water maze test were performed 1 week after Aβ1-42 injection to evaluate the ability of rat spacial learning and memory. Chrysophanol was intraperitoneally injected once daily for 5 consecutive days. After the behavioral tests, the animals were sacrificed immediately by decapitation, and the hippocampus were collected. The malondialdehyde (MDA) content and the activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) in the hippocampus were measured.RESULTS:Multiple (7 consecutive days, once daily) but not single (once a day) chrysophanol treatment at 1, 10 and 100 mg/kg effectively prevented Aβ1-42-induced cognitive function deficits in a dose-dependent manner as shown by Y-maze test and Morris water maze test. Moreover, the Aβ1-42-induced increase in MDA content and decrease in the activity of antioxidant enzymes (SOD, GSH-Px and CAT) in the hippocampus of the rats were also attenuated by multiple chrysophanol treatment.CONCLUSION:Repeated chrysophanol treatment attenuates Aβ1-42-induced cognitive deficits and synaptic plasticity dysfunction, and the mechanisms underlying the neuroprotective effects are likely due to its antioxidant activity.  相似文献   

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