Objective To observe the migration and differentiation of the neural precursor cells （NPCs） that derived from murine embryonic stem cells （ESCs） when they were transplanted into amyloid β （Aβ）-treated rat hipp...Objective To observe the migration and differentiation of the neural precursor cells （NPCs） that derived from murine embryonic stem cells （ESCs） when they were transplanted into amyloid β （Aβ）-treated rat hippocampus. Methods MESPU35, a murine ESC cell line that express the enhanced green fluorescent protein （EGFP）, was induced differentiation into nestin-positive NPCs by modified serum-free methods. The Aβ plaques and the differentiation of the grafted cells were observed by immunofluorescent staining. Results Comparing 16 weeks with 4 weeks post-transplantation, the migration distance increased about 5 times; the rate of migratory NPCs differentiating into glial fibrillary acidic protein （GFAP）-positive cells kept rising from （30.41 ± 1.45）% to （49.25± 1.23）%, and the rate of NPCs differentiating into neurofilament 200 （NF200） positive cells increased from （16.68±0.95）% to （27.94± 1.21）%. Meanwhile, the GFAP-positive cells targeting to the ipsilateral side of Aβ plaques increased from 60.2% to 81.3 %, while the NF200-positive cells increased from 61.3% to 84.1%. The migration distance had significant positive linear correlations to the neuronal differentiation rate （r = 0.991） and to the astrocytic differentiation rate （r = 0.953）. Conclusion Engrafted NPCs migrate targetedly to the Aβ injection site and differentiate into neurons and astrocytes.展开更多
Objective:To evaluate the diagnostic potential of cerebrospmal fluid (CSF) levels of β-amyloid protein (Aβ) as biochemical marker for senile dementia in clinical practice. Methods : Sensitive enzyme-linked immunosor...Objective:To evaluate the diagnostic potential of cerebrospmal fluid (CSF) levels of β-amyloid protein (Aβ) as biochemical marker for senile dementia in clinical practice. Methods : Sensitive enzyme-linked immunosorbent assay (ELISA) was performed in our lalxrratory to delect the CSF levels of Aβt-40, Aβ1-42 in 54 patients with Alzlteimer's disease (AD), and 30 normal controls (NC). Results: The cut off value of Aβ ratio and Aβ1-42 concentration in NC group provided 54. 51%, 90. 00% sensitivity and 81. 25%, 84. 38% specificity respectively in diagnosis of AD. Conclusion : AD group had a significant decreased level of Aβ1-42 and an increased level of Aβ ratio, compared with NC group.展开更多
Amyloid-β （Aβ） peptide, the primary constituent of senile plaques in Alzheimer＇s disease （AD）, is generated by β-secretase- and y-secretase-mediated sequential proteolysis of the amyloid precursor protein （AP...Amyloid-β （Aβ） peptide, the primary constituent of senile plaques in Alzheimer＇s disease （AD）, is generated by β-secretase- and y-secretase-mediated sequential proteolysis of the amyloid precursor protein （APP）. The aspartic protease, β -site APP cleavage enzyme （BACE）, has been identified as the main β-secretase in brain but the regulation of its activity is largely unclear. Here, we demonstrate that both BACE activity and subsequent Aβ production are enhanced after stimulation of receptor tyrosine kinases （RTKs）, such as the receptors for epidermal growth factor （EGF） and nerve growth factor （NGF）, in cultured cells as well as in mouse hippocampus. Furthermore, stimulation of RTKs also induces BACE internalization into endosomes and Golgi apparatus. This enhancement of BACE activity and A β production upon RTK activation could be specifically inhibited by Src family kinase inhibitors and by depletion of endogenous c-Src with RNAi, and could be mimicked by over-expressed c-Src. Moreover, blockage of BACE internalization by a dominant negative form of Rab5 also abolished the enhancement of BACE activity and Aβ production, indicating the requirement of BACE internalization for the enhanced activity. Taken together, our study presents evidence that BACE activity and Aβ production are under the regulation of RTKs and this is achieved via RTK-stimulated BACE internalization, and suggests that an aberration of such regulation might contribute to pathogenic Aβ production.展开更多
Alzheimer＇s disease （AD） is an increasing epidemic threatening public health. Both men and women are susceptible to the disease although women are at a slightly higher risk. The prevalence of AD rises exponentially...Alzheimer＇s disease （AD） is an increasing epidemic threatening public health. Both men and women are susceptible to the disease although women are at a slightly higher risk. The prevalence of AD rises exponentially in elderly people from 1% at age of 65 to approximately 40%-50% by the age of 95. While the cause of the disease has not been fully understood, genetics plays a role in the onset of the disease. Mutations in three genes （APP, PSENI, and PSEN2） have been found to cause AD and APOE4 allele increases the risk of the disease. As human genomic research progresses, more genes have been identified and linked with AD. Genetic screening tests for persons at high risk of AD are currently available and may help them as well as their families better prepare for a later life with AD.展开更多
Objective To investigate the proteolytic mechanism of amyloid precursor protein （APP） and to explore amyloidbeta （Aβ） generation in living neurons. Methods DNA fragments were amplified by PCR or synthesized. The ...Objective To investigate the proteolytic mechanism of amyloid precursor protein （APP） and to explore amyloidbeta （Aβ） generation in living neurons. Methods DNA fragments were amplified by PCR or synthesized. The four fragments, CFP, 54bp, YFP and C99 were ligated into pcDNA3.0 vector to construct the recombinant plasmids pcDNA3.0-CFP-54bp- YFP and pcDNA3.0-CFP-54bp-YFP-C99. The SH-SY5Y cells were transiently transfected with pcDNA3.0-CFP-54bp-YFP or pcDNA3.0-CFP-54bp-YFP-C99. The expression of fusion gene was examined under a multiphoton laser scanning microscope. Fluorescence resonance energy transfer （FRET） was used to measure the β cleavage and γ cleavage of APE Aβ generation was confirmed by immunocytochemistry and multiphoton laser scanning microscopy. Cell viability was tested by MTT assay at different time points. Results （1） The double restriction endonuclease digestion and sequencing analysis confirmed the authenticity of the recombinant plasmids pcDNA3.0-CFP-54bp-YFP and pcDNA3.0-CFP-54bp- YFP-C99. （2） Blue and yellow fluorescences were detected in the transfected cells. （3） FRET occurred in pcDNA3.0-CFP- 54bp-YFP-transfected cells but not in pcDNA3.0-CFP-54bp-YFP-C99-transfected cells. （4） Aβ was produced in the pcDNA3.0- CFP-54bp-YFP-C99 transfected cells. （5） Aβ-deposition was widespread in the cell. （6） Cell viability decreased along with the intracellular Aβ deposition. Conclusion C99 is important for the APP β cleavage. Aβ may be generated and deposited in cells at the early stage of Alzheimer＇s disease. Intracellular Aβ accumulation brings deleterious effects on cells.展开更多
The interaction between Amyloid β(Aβ) peptide and acetylcholine receptor is the key for our understanding of how Aβ fragments block the ion channels within the synapses and thus induce Alzheimer’s disease.Here,mol...The interaction between Amyloid β(Aβ) peptide and acetylcholine receptor is the key for our understanding of how Aβ fragments block the ion channels within the synapses and thus induce Alzheimer’s disease.Here,molecular docking and molecular dynamics(MD)simulations were performed for the structural dynamics of the docking complex consisting of Aβ and α7-n ACh R(α7 nicotinic acetylcholine receptor),and the inter-molecular interactions between ligand and receptor were revealed.The results show that Aβ_(25-35) is bound toα7-n ACh R through hydrogen bonds and complementary shape,and the Aβ_(25-35) fragments would easily assemble in the ion channel of α7-n ACh R,then block the ion transfer process and induce neuronal apoptosis.The simulated amide-I band of Aβ_(25-35) in the complex is located at 1650.5 cm^(-1),indicating the backbone of Aβ_(25-35) tends to present random coil conformation,which is consistent with the result obtained from cluster analysis.Currently existing drugs were used as templates for virtual screening,eight new drugs were designed and semi-flexible docking was performed for their performance.The results show that,the interactions between new drugs and α7-n ACh R are strong enough to inhibit the aggregation of Aβ_(25-35) fragments in the ion channel,and also be of great potential in the treatment of Alzheimer’s disease.展开更多
The Alzheimer＇s disease （AD） is one of the common cognitive disorders in the elderly. AD shares some similar pathological characters with diabetes mellitus （DM）, suggesting potential application of anti-diabetic ...The Alzheimer＇s disease （AD） is one of the common cognitive disorders in the elderly. AD shares some similar pathological characters with diabetes mellitus （DM）, suggesting potential application of anti-diabetic agents, such as vanadyl complexes, in therapeutic treatment of AD. In the present work, we studied the effects of vanadyl acetylacetonate （VO（acac）2） and cinnamaldehyde （CA） on an AD model based on SH-SY5Y neural cells. The experimental results showed that VO（acac）2 at sub-micromolar concentrations could improve the viability of neural cells with or without increased β-amyloid （Aβ） burden; and the combination of VO（acac）2 and CA showed an additive cell protection effects. Further investigation revealed that for SH-SY5Y neural cells, VO（acac）2 could activate PPART-AMPK signal transduction and inhibit GSK 3β, one of the major kinases for Tau hyperphosphorylation. Meanwhile, CA could correct the abnormal mitochondrial morphology due to Aβ-induced excessive mitochondrial fission, thus restoring/enhancing the mitochondrial function. In addition, both VO（acac）2 and CA decreased intracellular reactive oxygen species （ROS） level and inhibited formation of toxic Aβ oligomers. Overall, VO（acac）2 might work with CA in improving the neural cell viability under the Aβ burden, suggesting application of vanadium metallodrugs in AD treatment.展开更多
OBJECTIVE： To investigate the effect of Bushenyisui Formula on cell apoptosis and positive B cell lym- phoma （Bcl-2） in the Brain of rat models of Alzheim- er＇s disease （AD） induced by beta-amyloid protein （All...OBJECTIVE： To investigate the effect of Bushenyisui Formula on cell apoptosis and positive B cell lym- phoma （Bcl-2） in the Brain of rat models of Alzheim- er＇s disease （AD） induced by beta-amyloid protein （All3） and the mechanism underlying the effect. METHODS： Total of 40 SD rats, 20 females and 20 males, were randomly assigned to 4 groups, con- trolled group （A）, model group （B）, conventional treatment group （C） and Bushenyisui Formula treat- ment （BYFT） group （D）, 10 rats in each group. AI3 1-42 was injected into the bilateral hippocampus of the rats in group B, C and D to create the models of AD. Sham operation was performed on the rats of group A in the same way by injecting equal volume of 0.9% sodium chloride solution into their bilateral hippocampus. 5 days after operation, Bushenyisui Formula was intraperitoneally administered at a dose of 450 mg/kg to the rats of group D （QD） for 20 days. Equal volume of 0.9% sodium chloride solution was intraperitoneally injected into the rats of group B with the same procedure. C suspension （20 mg/mL） was intraperitoneally injected into the rats of group B with the same procedure. The number of apoptot- ic cells in Brain and the positive Bcl-2 were count- ed. The changes of learning and memory abilities were evaluated using Y-maze. RESULTS： Right after the establishment of the mod- els, group B, C and D compared to group A respec- tively, the outcomes of Y-maze were significantly different from that of group A, which suggested ob- vious learning and memory disorder in those groups （P〈0.01）. After treatment, the times of elec- tronic shocks of group C and D were significantly less than that of group B （P〈0.05）, and the numbers of apoptotic cells and positive Bcl-2 were signifi- cantly different from those of group B, apoptotic sells＇ number of group C and D smaller than that of group B and the number of positive Bcl-2 greater than that of group B. CONCLUSION： Bushenyisui Formula could increase the number of Bcl-2 in brain, which improved the function of nervous system pertaining to learning and memory abilities.展开更多
Objective： To investigate the relationship between post-operative cognitive dysfunction（POCD） and regional cerebral oxygen saturation（rSO2） and β-amyloid protein（Aβ） in patients undergoing laparoscopic pancre...Objective： To investigate the relationship between post-operative cognitive dysfunction（POCD） and regional cerebral oxygen saturation（rSO2） and β-amyloid protein（Aβ） in patients undergoing laparoscopic pancreaticoduodenectomy. Methods： Fifty patients undergoing elective laparoscopic pancreaticoduodenectomy received five groups of neuropsychological tests 1 d pre-operatively and 7 d post-operatively, with continuous monitoring of rSO2 intra-operatively. Before anesthesia induction（t0）, at the beginning of laparoscopy（t1）, and at the time of pneumoperitoneum 120 min（t2）, pneumoperitoneum 240 min（t3）, pneumoperitoneum 480 min（t4）, the end of pneumoperitoneum（t5）, and 24 h after surgery, jugular venous blood was drawn respectively for the measurement of Aβ by enzyme-linked immunosorbent assay（ELISA）. Results： Twenty-one cases of the fifty patients suffered from POCD after operation. We found that the maximum percentage drop in rSO2（rSO2, %max） was significantly higher in the POCD group than in the non-POCD group. The rSO2, %max value of over 10.2% might be a potential predictor of neurocognitive injury for those patients. In the POCD group, the plasma Aβ levels after 24 h were significantly higher than those of pre-operative values（P〈0.01）. After 24 h, levels of plasma Aβ in the POCD group were significantly higher than those in the non-POCD group（P〈0.01）. Conclusions： The development of POCD in patients undergoing laparoscopic pancreaticoduodenectomy is associated with alterations of rSO2 and Aβ. Monitoring of rSO2 might be useful in the prediction of POCD, and Aβ might be used as a sensitive biochemical marker to predict the occurrence of POCD.展开更多
Accumulating evidence suggests that β-amyloid （Aβ）-induced neuroinflammation plays a prominent and early role in Alzheimer＇s disease （AD）. In this study, we demonstrated that Presenilin 2 （PS2） deficiency fac...Accumulating evidence suggests that β-amyloid （Aβ）-induced neuroinflammation plays a prominent and early role in Alzheimer＇s disease （AD）. In this study, we demonstrated that Presenilin 2 （PS2） deficiency facilitates Aβ-induced neuroinflammation and injury by upregulating P2X7 expression both in vitro and in vivo. PS2 knockout mice demonstrated increased cognitive impairments and cerebral injury. PS2 deficiency increased the expression of P2X7 both in neurons and microglial cells. Furthermore, extracellular ATP also increased in both Aβ-treated and untreated PS2 knockout microglial cells. Notably, Aβ-induced classical proinflammatory cytokines such as IL-113, IL-1α and TNF-α were increased in PS2 knockout microglial cells, suggesting a potential role for PS2 in the regulation of neuroinflammation. The expression of P2X7 clearly increased in PS2 knockdown BV2 cells. Consistent with in vivo data, Aβ-induced IL-1βproduction was also clearly enhanced in PS2 knockdown BV2 cells. Additionally, expression of the transcription factor Sp was increased in PS2 knockdown cells. When we treated PS2 knockdown ceils with the specific Spl inhibitor MIT, we observed that enhanced P2X7 expression was significantly rescued. Taken together, these data suggests that PS2 plays a protective role during Aβ-induced neuroinflammation and injury through down-regulation of P2X7 expression.展开更多
Objective： To explore influence of electroacupuncture（EA） therapy of tonifying the kidney and regulating governor vessel on amyloid beta（Aβ） related degradation enzymes in the hippocampus of a rat model of Alzhe...Objective： To explore influence of electroacupuncture（EA） therapy of tonifying the kidney and regulating governor vessel on amyloid beta（Aβ） related degradation enzymes in the hippocampus of a rat model of Alzheimer＇s disease（AD） induced by Aβ（1-42）.Methods： Forty Wistar male rats were randomly divided into 4 groups： a normal group, a sham operation group, a model group and an EA group, 10 rats in each one. The rats in normal group were normally fed. The rats in sham operation group were bilaterally injected in the hippocampus with 5 μL of saline and they were normally fed after the injection. The rats in the model group and the EA group were bilaterally injected in the hippocampus with 5 μL of Aβ（1-42） on each side. Rats in the EA group received EA of 5 Hz continuous wave at the ＂Bǎihuì（百会 GV20）＂ and bilateral ＂Shènshū（肾俞 BL23）＂ for a duration of 15 min per time every day and continuously for 15 days. After 15 days, the hippocampal expression levels of insulin degrading enzyme（IDE）, lipoprotein（LPL）, transthyretin（TTR）, apolipoprotein E（APoE）,a2 macroglobulin（a2 M） and Aβ（1-42） of the 4 groups were tested by Western blot.Results： Compared with the sham operation group, the expression levels of IDE, LPL, TTR, APoE and a2 M in the hippocampus were significantly lower（P〈 0.05, P〈 0.01） and the expression of Aβ（1-42） was significantly higher（P〈 0.01） in the model group. Compared with the model group, the expression levels of IDE, LPL, TTR,APoE and a2 M in the hippocampus of these rats were significantly lower（P〈 0.05,P〈 0.01）, the expression of Aβ（1-42） was significantly higher（P〈 0.01） in the EA group.Conclusion： EA therapy of tonifying the kidney and regulating governor vessel can enhance the expression of IDE, LPL, TTR, APoE, and a2 M in the hippocampus of AD rats injected by Aβ（1-42）, and may consequently promote the degradation of aβ（1-42） to help improve the pathological manifestations of AD and therefore delay its progression.展开更多
基金This work was supported by the National Natural Science Foundation of China （No. 30571770）.
文摘Objective To observe the migration and differentiation of the neural precursor cells （NPCs） that derived from murine embryonic stem cells （ESCs） when they were transplanted into amyloid β （Aβ）-treated rat hippocampus. Methods MESPU35, a murine ESC cell line that express the enhanced green fluorescent protein （EGFP）, was induced differentiation into nestin-positive NPCs by modified serum-free methods. The Aβ plaques and the differentiation of the grafted cells were observed by immunofluorescent staining. Results Comparing 16 weeks with 4 weeks post-transplantation, the migration distance increased about 5 times; the rate of migratory NPCs differentiating into glial fibrillary acidic protein （GFAP）-positive cells kept rising from （30.41 ± 1.45）% to （49.25± 1.23）%, and the rate of NPCs differentiating into neurofilament 200 （NF200） positive cells increased from （16.68±0.95）% to （27.94± 1.21）%. Meanwhile, the GFAP-positive cells targeting to the ipsilateral side of Aβ plaques increased from 60.2% to 81.3 %, while the NF200-positive cells increased from 61.3% to 84.1%. The migration distance had significant positive linear correlations to the neuronal differentiation rate （r = 0.991） and to the astrocytic differentiation rate （r = 0.953）. Conclusion Engrafted NPCs migrate targetedly to the Aβ injection site and differentiate into neurons and astrocytes.
基金Supported by Grant from National Ministry of Personnel Foundation for Distinguished Young Schotars of China(1998)
文摘Objective:To evaluate the diagnostic potential of cerebrospmal fluid (CSF) levels of β-amyloid protein (Aβ) as biochemical marker for senile dementia in clinical practice. Methods : Sensitive enzyme-linked immunosorbent assay (ELISA) was performed in our lalxrratory to delect the CSF levels of Aβt-40, Aβ1-42 in 54 patients with Alzlteimer's disease (AD), and 30 normal controls (NC). Results: The cut off value of Aβ ratio and Aβ1-42 concentration in NC group provided 54. 51%, 90. 00% sensitivity and 81. 25%, 84. 38% specificity respectively in diagnosis of AD. Conclusion : AD group had a significant decreased level of Aβ1-42 and an increased level of Aβ ratio, compared with NC group.
基金grants from the Ministry of Science and Technology （2003CB515405, 2005CB522406） the National Natural Science Foundation of China （30021003, 30400230, 30625014）+2 种基金 the Chinese Academy of Sciences （KSCX1- SW, KSCX2-SW） the Ministry of Education, Shanghai Municipal Commission for Science and Technology （06ZR14098） China Post Doctoral Science Foundation, and Shanghai Postdoctoral Science Foundation.
文摘Amyloid-β （Aβ） peptide, the primary constituent of senile plaques in Alzheimer＇s disease （AD）, is generated by β-secretase- and y-secretase-mediated sequential proteolysis of the amyloid precursor protein （APP）. The aspartic protease, β -site APP cleavage enzyme （BACE）, has been identified as the main β-secretase in brain but the regulation of its activity is largely unclear. Here, we demonstrate that both BACE activity and subsequent Aβ production are enhanced after stimulation of receptor tyrosine kinases （RTKs）, such as the receptors for epidermal growth factor （EGF） and nerve growth factor （NGF）, in cultured cells as well as in mouse hippocampus. Furthermore, stimulation of RTKs also induces BACE internalization into endosomes and Golgi apparatus. This enhancement of BACE activity and A β production upon RTK activation could be specifically inhibited by Src family kinase inhibitors and by depletion of endogenous c-Src with RNAi, and could be mimicked by over-expressed c-Src. Moreover, blockage of BACE internalization by a dominant negative form of Rab5 also abolished the enhancement of BACE activity and Aβ production, indicating the requirement of BACE internalization for the enhanced activity. Taken together, our study presents evidence that BACE activity and Aβ production are under the regulation of RTKs and this is achieved via RTK-stimulated BACE internalization, and suggests that an aberration of such regulation might contribute to pathogenic Aβ production.
文摘Alzheimer＇s disease （AD） is an increasing epidemic threatening public health. Both men and women are susceptible to the disease although women are at a slightly higher risk. The prevalence of AD rises exponentially in elderly people from 1% at age of 65 to approximately 40%-50% by the age of 95. While the cause of the disease has not been fully understood, genetics plays a role in the onset of the disease. Mutations in three genes （APP, PSENI, and PSEN2） have been found to cause AD and APOE4 allele increases the risk of the disease. As human genomic research progresses, more genes have been identified and linked with AD. Genetic screening tests for persons at high risk of AD are currently available and may help them as well as their families better prepare for a later life with AD.
文摘Objective To investigate the proteolytic mechanism of amyloid precursor protein （APP） and to explore amyloidbeta （Aβ） generation in living neurons. Methods DNA fragments were amplified by PCR or synthesized. The four fragments, CFP, 54bp, YFP and C99 were ligated into pcDNA3.0 vector to construct the recombinant plasmids pcDNA3.0-CFP-54bp- YFP and pcDNA3.0-CFP-54bp-YFP-C99. The SH-SY5Y cells were transiently transfected with pcDNA3.0-CFP-54bp-YFP or pcDNA3.0-CFP-54bp-YFP-C99. The expression of fusion gene was examined under a multiphoton laser scanning microscope. Fluorescence resonance energy transfer （FRET） was used to measure the β cleavage and γ cleavage of APE Aβ generation was confirmed by immunocytochemistry and multiphoton laser scanning microscopy. Cell viability was tested by MTT assay at different time points. Results （1） The double restriction endonuclease digestion and sequencing analysis confirmed the authenticity of the recombinant plasmids pcDNA3.0-CFP-54bp-YFP and pcDNA3.0-CFP-54bp- YFP-C99. （2） Blue and yellow fluorescences were detected in the transfected cells. （3） FRET occurred in pcDNA3.0-CFP- 54bp-YFP-transfected cells but not in pcDNA3.0-CFP-54bp-YFP-C99-transfected cells. （4） Aβ was produced in the pcDNA3.0- CFP-54bp-YFP-C99 transfected cells. （5） Aβ-deposition was widespread in the cell. （6） Cell viability decreased along with the intracellular Aβ deposition. Conclusion C99 is important for the APP β cleavage. Aβ may be generated and deposited in cells at the early stage of Alzheimer＇s disease. Intracellular Aβ accumulation brings deleterious effects on cells.
基金supported by the National Natural Science Foundation of China(No.21103021)the New Century Excellent Talent Project in University of Fujian Province,Opening Project of PCOSS,Xiamen University(No.201904)。
文摘The interaction between Amyloid β(Aβ) peptide and acetylcholine receptor is the key for our understanding of how Aβ fragments block the ion channels within the synapses and thus induce Alzheimer’s disease.Here,molecular docking and molecular dynamics(MD)simulations were performed for the structural dynamics of the docking complex consisting of Aβ and α7-n ACh R(α7 nicotinic acetylcholine receptor),and the inter-molecular interactions between ligand and receptor were revealed.The results show that Aβ_(25-35) is bound toα7-n ACh R through hydrogen bonds and complementary shape,and the Aβ_(25-35) fragments would easily assemble in the ion channel of α7-n ACh R,then block the ion transfer process and induce neuronal apoptosis.The simulated amide-I band of Aβ_(25-35) in the complex is located at 1650.5 cm^(-1),indicating the backbone of Aβ_(25-35) tends to present random coil conformation,which is consistent with the result obtained from cluster analysis.Currently existing drugs were used as templates for virtual screening,eight new drugs were designed and semi-flexible docking was performed for their performance.The results show that,the interactions between new drugs and α7-n ACh R are strong enough to inhibit the aggregation of Aβ_(25-35) fragments in the ion channel,and also be of great potential in the treatment of Alzheimer’s disease.
基金National Natural Science Foundation of China(Grant No.21571006 and 21271012)
文摘The Alzheimer＇s disease （AD） is one of the common cognitive disorders in the elderly. AD shares some similar pathological characters with diabetes mellitus （DM）, suggesting potential application of anti-diabetic agents, such as vanadyl complexes, in therapeutic treatment of AD. In the present work, we studied the effects of vanadyl acetylacetonate （VO（acac）2） and cinnamaldehyde （CA） on an AD model based on SH-SY5Y neural cells. The experimental results showed that VO（acac）2 at sub-micromolar concentrations could improve the viability of neural cells with or without increased β-amyloid （Aβ） burden; and the combination of VO（acac）2 and CA showed an additive cell protection effects. Further investigation revealed that for SH-SY5Y neural cells, VO（acac）2 could activate PPART-AMPK signal transduction and inhibit GSK 3β, one of the major kinases for Tau hyperphosphorylation. Meanwhile, CA could correct the abnormal mitochondrial morphology due to Aβ-induced excessive mitochondrial fission, thus restoring/enhancing the mitochondrial function. In addition, both VO（acac）2 and CA decreased intracellular reactive oxygen species （ROS） level and inhibited formation of toxic Aβ oligomers. Overall, VO（acac）2 might work with CA in improving the neural cell viability under the Aβ burden, suggesting application of vanadium metallodrugs in AD treatment.
文摘OBJECTIVE： To investigate the effect of Bushenyisui Formula on cell apoptosis and positive B cell lym- phoma （Bcl-2） in the Brain of rat models of Alzheim- er＇s disease （AD） induced by beta-amyloid protein （All3） and the mechanism underlying the effect. METHODS： Total of 40 SD rats, 20 females and 20 males, were randomly assigned to 4 groups, con- trolled group （A）, model group （B）, conventional treatment group （C） and Bushenyisui Formula treat- ment （BYFT） group （D）, 10 rats in each group. AI3 1-42 was injected into the bilateral hippocampus of the rats in group B, C and D to create the models of AD. Sham operation was performed on the rats of group A in the same way by injecting equal volume of 0.9% sodium chloride solution into their bilateral hippocampus. 5 days after operation, Bushenyisui Formula was intraperitoneally administered at a dose of 450 mg/kg to the rats of group D （QD） for 20 days. Equal volume of 0.9% sodium chloride solution was intraperitoneally injected into the rats of group B with the same procedure. C suspension （20 mg/mL） was intraperitoneally injected into the rats of group B with the same procedure. The number of apoptot- ic cells in Brain and the positive Bcl-2 were count- ed. The changes of learning and memory abilities were evaluated using Y-maze. RESULTS： Right after the establishment of the mod- els, group B, C and D compared to group A respec- tively, the outcomes of Y-maze were significantly different from that of group A, which suggested ob- vious learning and memory disorder in those groups （P〈0.01）. After treatment, the times of elec- tronic shocks of group C and D were significantly less than that of group B （P〈0.05）, and the numbers of apoptotic cells and positive Bcl-2 were signifi- cantly different from those of group B, apoptotic sells＇ number of group C and D smaller than that of group B and the number of positive Bcl-2 greater than that of group B. CONCLUSION： Bushenyisui Formula could increase the number of Bcl-2 in brain, which improved the function of nervous system pertaining to learning and memory abilities.
基金Project supported by the Shandong Science and Technology Development Project(No.2011YD18070),China
文摘Objective： To investigate the relationship between post-operative cognitive dysfunction（POCD） and regional cerebral oxygen saturation（rSO2） and β-amyloid protein（Aβ） in patients undergoing laparoscopic pancreaticoduodenectomy. Methods： Fifty patients undergoing elective laparoscopic pancreaticoduodenectomy received five groups of neuropsychological tests 1 d pre-operatively and 7 d post-operatively, with continuous monitoring of rSO2 intra-operatively. Before anesthesia induction（t0）, at the beginning of laparoscopy（t1）, and at the time of pneumoperitoneum 120 min（t2）, pneumoperitoneum 240 min（t3）, pneumoperitoneum 480 min（t4）, the end of pneumoperitoneum（t5）, and 24 h after surgery, jugular venous blood was drawn respectively for the measurement of Aβ by enzyme-linked immunosorbent assay（ELISA）. Results： Twenty-one cases of the fifty patients suffered from POCD after operation. We found that the maximum percentage drop in rSO2（rSO2, %max） was significantly higher in the POCD group than in the non-POCD group. The rSO2, %max value of over 10.2% might be a potential predictor of neurocognitive injury for those patients. In the POCD group, the plasma Aβ levels after 24 h were significantly higher than those of pre-operative values（P〈0.01）. After 24 h, levels of plasma Aβ in the POCD group were significantly higher than those in the non-POCD group（P〈0.01）. Conclusions： The development of POCD in patients undergoing laparoscopic pancreaticoduodenectomy is associated with alterations of rSO2 and Aβ. Monitoring of rSO2 might be useful in the prediction of POCD, and Aβ might be used as a sensitive biochemical marker to predict the occurrence of POCD.
基金supported by the National Natural Science Foundation of China (31470040, 31570896, 81172816, 81672811)Doctoral Fund of Ministry of Education of China (20130076110013)Science and Technology Commission of Shanghai Municipality(15JC1401500)
文摘Accumulating evidence suggests that β-amyloid （Aβ）-induced neuroinflammation plays a prominent and early role in Alzheimer＇s disease （AD）. In this study, we demonstrated that Presenilin 2 （PS2） deficiency facilitates Aβ-induced neuroinflammation and injury by upregulating P2X7 expression both in vitro and in vivo. PS2 knockout mice demonstrated increased cognitive impairments and cerebral injury. PS2 deficiency increased the expression of P2X7 both in neurons and microglial cells. Furthermore, extracellular ATP also increased in both Aβ-treated and untreated PS2 knockout microglial cells. Notably, Aβ-induced classical proinflammatory cytokines such as IL-113, IL-1α and TNF-α were increased in PS2 knockout microglial cells, suggesting a potential role for PS2 in the regulation of neuroinflammation. The expression of P2X7 clearly increased in PS2 knockdown BV2 cells. Consistent with in vivo data, Aβ-induced IL-1βproduction was also clearly enhanced in PS2 knockdown BV2 cells. Additionally, expression of the transcription factor Sp was increased in PS2 knockdown cells. When we treated PS2 knockdown ceils with the specific Spl inhibitor MIT, we observed that enhanced P2X7 expression was significantly rescued. Taken together, these data suggests that PS2 plays a protective role during Aβ-induced neuroinflammation and injury through down-regulation of P2X7 expression.
基金Supported by National Natural Science Foundation of China Project:No.81473786
文摘Objective： To explore influence of electroacupuncture（EA） therapy of tonifying the kidney and regulating governor vessel on amyloid beta（Aβ） related degradation enzymes in the hippocampus of a rat model of Alzheimer＇s disease（AD） induced by Aβ（1-42）.Methods： Forty Wistar male rats were randomly divided into 4 groups： a normal group, a sham operation group, a model group and an EA group, 10 rats in each one. The rats in normal group were normally fed. The rats in sham operation group were bilaterally injected in the hippocampus with 5 μL of saline and they were normally fed after the injection. The rats in the model group and the EA group were bilaterally injected in the hippocampus with 5 μL of Aβ（1-42） on each side. Rats in the EA group received EA of 5 Hz continuous wave at the ＂Bǎihuì（百会 GV20）＂ and bilateral ＂Shènshū（肾俞 BL23）＂ for a duration of 15 min per time every day and continuously for 15 days. After 15 days, the hippocampal expression levels of insulin degrading enzyme（IDE）, lipoprotein（LPL）, transthyretin（TTR）, apolipoprotein E（APoE）,a2 macroglobulin（a2 M） and Aβ（1-42） of the 4 groups were tested by Western blot.Results： Compared with the sham operation group, the expression levels of IDE, LPL, TTR, APoE and a2 M in the hippocampus were significantly lower（P〈 0.05, P〈 0.01） and the expression of Aβ（1-42） was significantly higher（P〈 0.01） in the model group. Compared with the model group, the expression levels of IDE, LPL, TTR,APoE and a2 M in the hippocampus of these rats were significantly lower（P〈 0.05,P〈 0.01）, the expression of Aβ（1-42） was significantly higher（P〈 0.01） in the EA group.Conclusion： EA therapy of tonifying the kidney and regulating governor vessel can enhance the expression of IDE, LPL, TTR, APoE, and a2 M in the hippocampus of AD rats injected by Aβ（1-42）, and may consequently promote the degradation of aβ（1-42） to help improve the pathological manifestations of AD and therefore delay its progression.
