Dendrobium nobile Lindl.alkaloids（DNLA）,the active ingredients of a traditional Chinese medicine Dendrobium,have been shown to have anti-oxidative effects,anti-inflammatory action,and protective effect on neurons ag...Dendrobium nobile Lindl.alkaloids（DNLA）,the active ingredients of a traditional Chinese medicine Dendrobium,have been shown to have anti-oxidative effects,anti-inflammatory action,and protective effect on neurons against oxygen-glucose deprivation.However,it is not clear whether DNLA reduces amyloid-beta（Aβ）-induced neuronal injury.In this study,cortical neurons were treated with DNLA at different concentrations（0.025,0.25,and 2.5 mg/L）for 24 hours,followed by administration of Aβ（25-35）（10μM）.Aβ（25-35） treatments increased cell injury as determined by the leakage of lactate dehydrogenase,which was accompanied by chromatin condensation and mitochondrial tumefaction.The damage caused by Aβ（25-35） on these cellular properties was markedly attenuated when cells were pretreated with DNLA.Treatment with Aβ（25-35）down-regulated the expressions of postsynaptic density-95 mRNA and decreased the protein expression of synaptophysin and postsynaptic density-95,all changes were significantly reduced by pretreatment of cells with DNLA.These findings suggest that DNLA reduces the cytotoxicity induced by Aβ（25-35） in rat primary cultured neurons.The protective mechanism that DNLA confers on the synaptic integrity of cultured neurons might be mediated,at least in part,through the upregulation of neurogenesis related proteins synaptophysin and postsynaptic density-95.展开更多
e-related macular degeneration （AMD） causes irreversible loss of central vision for which there is no effective treatment. Incipient pathology is thought to occur in the retina for many years before AMD manifests fr...e-related macular degeneration （AMD） causes irreversible loss of central vision for which there is no effective treatment. Incipient pathology is thought to occur in the retina for many years before AMD manifests from midlife onwards to affect a large proportion of the elderly. Although genetic as well as non-genetic/environmental risks are recognized, its complex aetiology makes it difficult to identify susceptibility, or indeed what type of AMD develops or how quickly it progresses in different individuals. Here we summarize the literature describing how the Alzheimer＇s-linked amyloid beta （Aβ） group of misfolding proteins accumulate in the retina. The discovery of this key driver of Alzheimer＇s disease in the senescent retina was unexpected and surprising, enabling an altogether different perspective of AMD. We argue that Aβ fundamentally differs from other substances which accumulate in the ageing retina, and discuss our latest findings from a mouse model in which physiological amounts of Aβ were subretinally-injected to recapitulate salient features of early AMD within a short period. Our discoveries as well as those of others suggest the pattern of Aβ accumulation and pathology in donor aged/AMD tissues are closely reproduced in mice, including late-stage AMD phenotypes, which makes them highly attractive to study dynamic aspects of Aβ-mediated retinopathy. Furthermore, we discuss our findings revealing how Aβ behaves at single-cell resolution, and consider the long-term implications for neuroretinal function. We propose Aβ as a key element in switching to a diseased retinal phenotype, which is now being used as a biomarker for latestage AMD.展开更多
As an aging-associated degenerative disease,Alzheimer’s disease is characterized by the deposition of amyloid beta(Aβ),oxidative stress,inflammation,dysfunction and loss of cholinergic neurons.Colla Corii Asini(CCA)...As an aging-associated degenerative disease,Alzheimer’s disease is characterized by the deposition of amyloid beta(Aβ),oxidative stress,inflammation,dysfunction and loss of cholinergic neurons.Colla Corii Asini(CCA)is a traditional Chinese medicine which has been used for feebleness-related diseases and anti-aging.CCA might delay aging-induced degenerative changes in neurons.In the present study,we evaluated antioxidant activity,cytoprotective effects,and Aβremovability of enzyme-digested Colla Corii Asini(CCAD).Oxygen radical absorbance capacity(ORAC)activity assay showed that,as compared to gelatins from the skin of porcine,bovine and cold water fish,CCA exhibited the highest ORAC activity.The ORAC activity of CCA and CCAD was increased gradually by the length of time in storage.Ultrastructure analysis by scanning electron microscopy showed that among CCA manufactured in 2008,2013,2017 and gelatin from cold water fish skin,CCA manufactured in 2008 presented the smoothest surface structure.We further tested the protective effects of CCAD(manufactured in 2008)and enzyme-digested gelatin from cold water fish skin(FGD)on hydrogen peroxide(H2O2)-induced cell death in nerve growth factor-differentiated neuronal-like PC12 cells.Presto blue assay showed that both FGD and CCAD at 0.5 mg/m L increased cell viability in H2O2-treated neuronal-like PC12 cells.The protection of CCAD was significantly superior to that of FGD.Acetylcholinesterase(Ach E)assay showed that both FGD and CCAD inhibited Ach E activity in nerve growth factor-differentiated neuronal-like PC12 cells to 89.1%and 74.5%of that in non-treated cells,respectively.The data suggest that CCAD might be able to increase the neurotransmitter acetylcholine.Although CCAD inhibited Ach E activity in neuronal-like PC12 cells,CCAD prevented H2O2-induced abnormal deterioration of Ach E.ELISA and neprilysin activity assay results indicated that CCAD reduced amyloid beta accumulation and increased neprilysin activity in Aβ1–42-treated neuronal-like PC12 cells,suggesting that CCAD can enhance Aβclearance.Our results suggest that CCA might be useful for preventing and treating Alzheimer’s disease.展开更多
Mounting evidence indicates that amyloid β protein（Aβ） exerts neurotoxicity by disrupting the blood-brain barrier（BBB） in Alzheimer＇s disease. Hyperoside has neuroprotective effects both in vitro and in vivo ag...Mounting evidence indicates that amyloid β protein（Aβ） exerts neurotoxicity by disrupting the blood-brain barrier（BBB） in Alzheimer＇s disease. Hyperoside has neuroprotective effects both in vitro and in vivo against Aβ. Our previous study found that hyperoside suppressed Aβ1-42-induced leakage of the BBB, however, the mechanism remains unclear. In this study, bEnd.3 cells were pretreated with 50, 200, or 500 μM hyperoside for 2 hours, and then exposed to Aβ1-42 for 24 hours. Cell viability was determined using 3-（4,5-dimethyl-2-thiazolyl）-2,5-diphenyl-2-H-tetrazolium bromide assay. Flow cytometry and terminal deoxynucleotidyl transferase-mediated d UTP nick-end labeling assay were used to analyze cell apoptosis. Western blot assay was carried out to analyze expression levels of Bax, Bcl-2, cytochrome c, caspase-3, caspse-8, caspase-9, caspase-12, occludin, claudin-5, zonula occludens-1, matrix metalloproteinase-2（MMP-2）, and MMP-9. Exposure to Aβ1-42 alone remarkably induced bEnd.3 cell apoptosis; increased ratios of cleaved caspase-9/caspase-9, Bax/Bcl-2, cleav ed caspase-8/caspase-8, and cleaved caspase-12/caspase-12; increased expression of cytochrome c and activity of caspase-3; diminished levels of zonula occludens-1, claudin-5, and occludin; and increased levels of MMP-2 and MMP-9. However, hyperoside pretreatment reversed these changes in a dose-dependent manner. Our findings confirm that hyperoside alleviates fibrillar Aβ1-42-induced BBB disruption, thus offering a feasible therapeutic application in Alzheimer＇s disease.展开更多
Previous studies have shown that sirtuin 1（SIRT1） reduces the production of neuronal amyloid beta（Aβ） and inhibits the inflammatory response of glial cells, thereby generating a neuroprotective effect against Aβ...Previous studies have shown that sirtuin 1（SIRT1） reduces the production of neuronal amyloid beta（Aβ） and inhibits the inflammatory response of glial cells, thereby generating a neuroprotective effect against Aβ neurotoxicity in animal models of Alzheimer＇s disease. However, the protective effect of SIRT1 on astrocytes is still under investigation. This study established a time point model for the clearance of Aβ in primary astrocytes. Results showed that 12 hours of culture was sufficient for endocytosis of oligomeric Aβ, and 36 hours sufficient for effective degradation. Immunofluorescence demonstrated that Aβ degradation in primary astrocytes relies on lysosome function. Enzymatic agonists or SIRT1 inhibitors were used to stimulate cells over a concentration gradient. Aβ was co-cultured for 36 hours in medium. Western blot assay results under different conditions revealed that SIRT1 relies on its deacetylase activity to promote intracellular Aβ degradation. The experiment further screened SIRT1 using quantitative proteomics to investigate downstream, differentially expressed proteins in the Aβ degradation pathway and selected the ones related to enzyme activity of SIRT1. Most of the differentially expressed proteins detected are close to the primary astrocyte lysosomal pathway. Immunofluorescence staining demonstrated that SIRT1 relies on its deacetylase activity to upregulate lysosome number in primary astrocytes. Taken together, these findings confirm that SIRT1 relies on its deacetylase activity to upregulate lysosome number, thereby facilitating oligomeric Aβ degradation in primary astrocytes.展开更多
Scutellaria baicalensis stem-leaf total flavonoid might attenuate learning/memory impairment and neuronal loss in rats induced by amyloid beta-peptide. This study aimed to explore the effects of Scutellaria baicalensi...Scutellaria baicalensis stem-leaf total flavonoid might attenuate learning/memory impairment and neuronal loss in rats induced by amyloid beta-peptide. This study aimed to explore the effects of Scutellaria baicalensis stem-leaf total flavonoid on amyloid beta-peptide-induced neuronal apoptosis and the expression of apoptosis-related proteins in the rat hippocampus. Male Wistar rats were given intragastric administration of Scutellaria baicalensis stem-leaf total flavonoid, 50 or 100 mg/kg, once per day. On day 8 after administration, 10 pg amyloid beta-peptide （25-35） was injected into the bilateral hippocampus of rats to induce neuronal apoptosis. On day 20, hippocampal tissue was harvested and probed with the terminal deoxyribonucleotidyl transferase-mediated biotin-16-dUTP nick-end labeling assay. Scutellaria baicalensis stem-leaf total flavonoid at 50 and 100 mg/kg reduced neuronal apoptosis induced by amyloid beta-peptide （25-35） in the rat hippocampus. Immunohistochemistry and western blot assay revealed that expression of the pro-apoptotic protein Bax, cytochrome c and caspase-3 was significantly diminished by 50 and 100 mg/kg Scutellaria baicalensis stem-leaf total flavonoid, while expression of the anti-apoptotic protein Bcl-2 was increased. Moreover, 100 mg/kg Scutellana baicalensis stem-leaf total flavonoid had a more dramatic effect than the lower dosage. These experimental findings indicate that Scutellaria baicalensis stem-leaf total flavonoid dose-dependently attenuates neuronal apoptosis induced by amyloid beta-peptide in the hippocampus, and it might mediate this by regulating the expression of Bax, cytochrome c, caspase-3 and Bcl-2.展开更多
AIM：To identify the pathological role of amyloid beta（Aβ） deposition in retinal degeneration,and explore Aβ deposition on the retinal pigment epithelium cells（RPE） layer and the associated structural and functi...AIM：To identify the pathological role of amyloid beta（Aβ） deposition in retinal degeneration,and explore Aβ deposition on the retinal pigment epithelium cells（RPE） layer and the associated structural and functional changes in Alzheimer＇s disease transgenic mice.METHODS：RPE changes in the eyes of APPswe/PS1 transgenic and none transgenic（NTG） mice over 20 months old were examined.Histological changes were investigated via hematoxylin and eosin（H＆E） staining and transmission electron microscopy（TEM） examination,whereas the expression of amyloid precursor protein（APP）,Aβ,Zonula occludens-1（ZO-1） and Ionized calcium binding adaptor molecule-1（IBA-1） were investigated using immunohistochemistry and immunofluorescence techniques.All of the obtained results were quantitatively and statistically analyzed.RESULTS：In aged transgenic mice,an APP-positive immunoreaction and Aβ deposition were detected on the RPE layer but were undetectable in NTG mice.The RPE demonstrated some vacuole changes,shortened basal infoldings and basal deposition in histopathological examination and TEM tests,wherein irregular shapes were indicated by ZO-1 disorganization through fluorescence.Furthermore,IBA-1 positive cells were observed to have accumulated and infiltrated into the RPE layer and localized beneath the RPE/Bruch＇s membrane（Br M） complex,which was accompanied by an increase in BrM thickness in aged transgenic mice in comparison to NTG mice.The IBA-1 positive cells were found to be co-stained with Aβ deposition on the RPE flat mounts.CONCLUSION：The observed Aβ deposition in the RPE layer may cause RPE dysfunction,which is associated with microglia cells infiltration into the retina of aged transgenic mice,suggesting that Aβ deposition probably plays a significant role in RPE-related degenerative disease.展开更多
Telencephalin is a neural glycoprotein that reduces apoptosis induced by amyloid beta protein in the human neural tumor cell line PAJU. In this study, we examined the role of the ezrin/radixin/moesin protein family/ph...Telencephalin is a neural glycoprotein that reduces apoptosis induced by amyloid beta protein in the human neural tumor cell line PAJU. In this study, we examined the role of the ezrin/radixin/moesin protein family/phosphatidylinositol-3-kinase/protein kinase B pathway in this process. Western blot analysis demonstrated that telencephalin, phosphorylated ezrin/radixin/moesin and phosphatidylinositol-3-kinase/protein kinase B were not expressed in PAJU cells transfected with empty plasmid, while they were expressed in PAJU cells transfected with a telencephalin expression plasmid. After treatment with 1.0 nM amyloid beta protein 42, expression of telencephalin and phosphorylated phosphatidylinositol-3-kinase/protein kinase B in the transfected cells gradually diminished, while levels of phosphorylated ezrin/radixin/moesin increased. In addition, the high levels of telencephalin, phosphorylated ezrin/radixin/moesin and phosphatidylinositol-3-kinase/protein kinase B expression in PAJU cells transfected with a telencephalin expression plasmid could be suppressed by the phosphatidylinositol-3-kinase inhibitor LY294002. These findings indicate that telencephalin activates the ezrin/radixin/moesin family/phosphatidylinositol-3-kinase/protein kinase B pathway and protects PAJU cells from amyloid beta protein-induced apoptosis.展开更多
Targeting early steps in amyloid-beta production：Alzheimer’s disease（AD）has a long history as the＂amyloid deposit＂disorder.Many disorders are now known to be caused by proteinβ-sheet misfolding and aggregation...Targeting early steps in amyloid-beta production：Alzheimer’s disease（AD）has a long history as the＂amyloid deposit＂disorder.Many disorders are now known to be caused by proteinβ-sheet misfolding and aggregation（e.g.,Parkinson’s disease：α-synuclein;Huntington’s disease：Huntingtin;展开更多
BACKGROUND： The findings about the alterations in cerebrospinal fluid beta-amyloid protein （Aβ ） and apolipoprotein E （APOE） after subarachnoid hemorrhage indicate that they have significant correlation with pro...BACKGROUND： The findings about the alterations in cerebrospinal fluid beta-amyloid protein （Aβ ） and apolipoprotein E （APOE） after subarachnoid hemorrhage indicate that they have significant correlation with prognosis of patients. OBJECTⅣE： To observe the alterations in cerebrospinal fluid Aβ and ApoE after subarachnoid hemorrhage （SAH）. DESIGN： Contrast observation. SETTING： Department of Neurosurgery, the First Hospital of Lanzhou University. PARTICIPANTS： A total of 25 SAH patients including 16 males and 9 females aged from 13 to 72 years were selected form Department of Neurosurgery, the First Affiliated Hospital of Lanzhou University from October 2003 to February 2004. The Hunt-Hess grade ranged from Ⅰ to Ⅳ, and patients admitted hospital in 24 hours after invasion, affirmed by the brain CT scan and lumbar vertebra puncture, no other severe complications and important organs＇ functional defect and severe infection, no hematological system disease. METHODS- All admitted patients were collected CSF by lumbar vertebra puncture in 24 hours. The cerebrospinal fluid （CSF） of control group came from the admitted 15 patients of our hospital that have no nervous system disease. Aβ content was detected by enzyme linked immunosorbent assay （ELISA）, the kit was provided by the Central Laboratory of the First Hospital of Lanzhou University; ApoE concentration was detected by monoclone enzyme linked immunosorbent assay （ELISA）, the kit was provided by the Immunotechnique Research Institute of the Fourth Military Medical University. S100B concentration was detected by enzyme linked immunosorbent assay double antibody sandwich method, the kit was provided by the Physiological Research Room of the Fourth Military Medical University. The data were indicated on Mean±SD and were analyzed by SPSS 10.0 statistical package. All data were handled through test of significance variance analysis, and groups were compared through independent sampler t test. The concentration was handled through Pearson correlation analysis between Aβ and ApoE. The relationship between Aβ, ApoE concentration with pathogenetic condition and prognosis of the patients was handled through Spearman ranking correlation analysis. MAIN OUTCOME MEASURES：① The concentration of ApoE, Aβ and S100B after SAH in contrast to the control group in CSF by different Hunt-Hess and Glasgow Outcome Scale （GOS） grades; ② The level of correlation between ApoE and Aβ ; ③Correlation between ApoE and Aβ in pathogenetic condition and prognosis of the patients. RESULTS： All 25 SAH patients and 15 controls were involved in the final analysis. ① The concentration of ApoE, Aβ and S100B in CSF： The concentration of ApoE decreased after SAH in contrast to the control group [（0.46±0.007）, （0.85±0.11） μg/L, P 〈 0.01], the concentration of ApoE decreased after SAH in contrast to the control group [（5.36± 1.19）, （8.41± 1.60） μg/L, P 〈 0.01], and the concentration of S100B increased after SAH in contrast to the control group [（18.60±7.31）, （6.56±1.02） pg/L, P 〈 0.01]. ② The concentration of ApoE, Aβ and S100B in CSF after SAH on different Hunt-Hess and GOS grades： The concentration of Aβ in Hunt-Hess Ⅰ -Ⅲ grade was higher than Hunt-Hess Ⅳ, Ⅴ grade [（6.63 ± 1.25）, （3.35± 1.02） μg/L, P 〈 0.01], and the concentration of ApoE in Hunt-Hess Ⅰ- Ⅲ grade was higher than Hunt-Hess Ⅳ, Ⅴ grade [（0.56±0.07）, （0.38±0.04） μg/L, P 〈 0.05], the concentration of S100B in Hunt-Hess Ⅰ - Ⅲ grade was lower than Hunt-Hess Ⅳ - Ⅴ grade [（16.32±5.58）, （22.85±8.10） pg/L, P 〈 0.01]; the concentration of Aβ in GOS Ⅰ - Ⅲ grade was lower than GOS Ⅳ, Ⅴ grade [（3.76± 1.04）, （5.89±1.20） μg/L, P 〈 0.01], and the concentration of ApoE in GOS Ⅰ - Ⅲ grade was lower than GOS Ⅳ, Ⅴ grade [（0.32±0.02）, （0.58±0.07） μg/L, P 〈 0.011, and the concentration of S100B in GOS Ⅰ - Ⅲ grade was higher than GOS Ⅳ, Ⅴ grade [（25.36±9.70）, （14.33±6.69） pg/L, P 〈 0.01].③ The results of Pearson correlation analysis and Spearman ranking correlation analysis： There was significantly positive correlation between CSF Aβ concentration and clinical outcome （r=0.65, P 〈 0.01）, and the decrease in CSF Aβ concentration correlated significant with that of ApoE （r =0.85, P 〈 0.01）. CONCLUSION： There is a significant decrease in both Aβ and ApoE in the CSF after SAH, and there is significant correlation between CSF Aβ and ApoE concentration with clinical outcome, the interactions between these proteins may have important effects on SAH, ApoE and Aβ as surrogate markers for the outcome of patients with SAH.展开更多
Alzheimer’s disease（AD）is the most common form of age-related dementia with the latest report（World Alzheimer Report,2015）showing 46.8 million people are currently affected by dementia.That number is expected to ...Alzheimer’s disease（AD）is the most common form of age-related dementia with the latest report（World Alzheimer Report,2015）showing 46.8 million people are currently affected by dementia.That number is expected to double every 20 years unless there is effective therapeutic intervention.The 42 amino acid peptide known as amyloid beta（or Aβ）has been implicated as one of the main causative agents of AD after its discovery in plaques in 1985（Masters et al.,1985）.展开更多
Recent studies have demonstrated that Notch-1 expression is increased in the hippocampus of Alzheimer＇s disease patients. We speculate that Notch-1 signaling may be involved in PC12 cell apoptosis induced by amyloid ...Recent studies have demonstrated that Notch-1 expression is increased in the hippocampus of Alzheimer＇s disease patients. We speculate that Notch-1 signaling may be involved in PC12 cell apoptosis induced by amyloid beta-peptide （25-35） （Aβ25-35）. In the present study, PC12 cells were cultured with different doses （0, 0.1, 1.0, 10 and 100 nmol/L） of N-[N-（3,5-Difluorophenacetyl）-L-alanyl]-S-phenylglycine t-butyl ester, a Notch-1 signaling pathway inhibitor, for 30 minutes. Then cultured cells were induced with Aβ25-3s for 48 hours. Pretreatment of PC12 cells with high doses of N-[N-（3,5-Difluorophenacetyl）-L-alanyl]-S-phenylglycine t-butyl ester （〉 10 nmol/L） prolonged the survival of PC12 cells after Aβ25-35 induction, decreased the expression of apoptosis-related proteins caspase-3, -8, -9, increased the activity of oxidative stress-related superoxide dismutase and catalase, inhibited the production of active oxygen, and reduced nuclear factor kappa B expression. This study indicates that the Notch-1 signaling pathway plays a pivotal role in Aβ25-35-induced PC12 apoptosis.展开更多
Alzheimer’s disease(AD)is the most common progressive neurodegenerative disorder.It is often lethal and currently lacks a satisfactory therapy.The disease has a specific neuro-pathological profile:accumulation of pro...Alzheimer’s disease(AD)is the most common progressive neurodegenerative disorder.It is often lethal and currently lacks a satisfactory therapy.The disease has a specific neuro-pathological profile:accumulation of proteinaceous deposits in the brain–amyloid plaques(containingβ-amyloid peptides)and neurofibrillary tangles which are accumulation of a profusion of long stringy tangles of proteins called tau.Between the two highly recognized AD hypotheses,amyloid beta(Aβ)peptide aggregation and accumulation play a significant role and are considered as an important mechanism of AD pathology.Aβis a proteolytic product of amyloid precursor protein and genetic studies supported the relevance of Aβin AD pathogenesis.A large number of small molecules were studied for their ability to inhibit Aβ-aggregation in oligomer form or after fibrillization.However,the protein-misfolding process has certain setbacks which are inevitable due to the different morphology of protein.In recent years,it has been demonstrated that tau also plays a central role in pathogenesis of this disease.Moreover,abnormal post-translational modifications of tau,in particular,increases in acetylation at specific sites likely contribute to the toxicity of tau.Although it is evident that tau with these aberrant post-translational modifications likely facilitates neurodegeneration,the precise cellular mechanisms by which tau compromises neuronal function remain unknown.In addition,much remains to be learned about new interventions that might be developed to prevent or reduce the negative impact of tau posttranslational modifications-related damage.This review article addresses the key roles of amyloid beta and tau protein in AD as well as the possible therapeutic agents that can reduce the toxic levels of both the proteins,and thus providing beneficial effect for the AD patients.展开更多
Amyloid beta（Aβ）-induced oxidative stress is a major pathologic hallmark of Alzheimer＇s disease. Cyanidin, a natural flavonoid compound, is neuroprotective against oxidative damage-mediated degeneration. However, ...Amyloid beta（Aβ）-induced oxidative stress is a major pathologic hallmark of Alzheimer＇s disease. Cyanidin, a natural flavonoid compound, is neuroprotective against oxidative damage-mediated degeneration. However, its molecular mechanism remains unclear. Here, we investigated the effects of cyanidin pretreatment against Aβ-induced neurotoxicity in PC12 cells, and explored the underlying mechanisms. Cyanidin pretreatment significantly attenuated Aβ-induced cell mortality and morphological changes in PC12 cells. Mechanistically, cyanidin effectively blocked apoptosis induced by Aβ, by restoring the mitochondrial membrane potential via upregulation of Bcl-2 protein expression. Moreover, cyanidin markedly protected PC12 cells from Aβ-induced DNA damage by blocking reactive oxide species and superoxide accumulation. These results provide evidence that cyanidin suppresses Aβ-induced cytotoxicity, by preventing oxidative damage mediated by reactive oxide species, which in turn inhibits mitochondrial apoptosis. Our study demonstrates the therapeutic potential of cyanidin in the prevention of oxidative stress-mediated Aβ neurotoxicity.展开更多
An important marker in neurodegenerative Alzheimer’s disease (AD) is abnormal production of amyloid beta (Aβ) peptide leading to formation of plaques in the brain. Through decreasing Aβ aggregates, anti-inflammator...An important marker in neurodegenerative Alzheimer’s disease (AD) is abnormal production of amyloid beta (Aβ) peptide leading to formation of plaques in the brain. Through decreasing Aβ aggregates, anti-inflammatory agents, phagocytosis, and proteolytic enzymes are known to decline risk of Aβ plaque formation. In the previous study we showed that aqueous extract of Lavandula angustifolia (lavender), with known anti-inflammatory effects, improves memory deficits in animal model of Alzheimer. Here, we assess if lavender play a role in clearance of Aβ plaques in the hippocampus. The Alzheimeric animals were created with intracerebroventricular injection of Aβ 1-42. To confirm formation of Aβ plaques, brain sections were stained by Congo red method. Twenty days post-injection they were administered with different doses (50, 100 and 200 mg/kg) of the aqueous extract of lavender for duration of 20 days. Our results demonstrated that 50 mg/kg of lavender not effectively influenced the Aβ plaques. On the other hand, the herbal medicine at the doses of 100 and 200 mg/kg markedly decreased the extent of Aβ aggregates. We concluded that the lavender extract dose dependently underlies elimination of Aβ plaques. The exact mechanism by which the herbal medicine removes the Aβ aggregates needs to be elucidated.展开更多
Neurovascular dysfunction,as an integral part of Alzheimer's disease,may have an important influence on the onset and progression of chronic neurodegenerative processes.The bloodbrain barrier(BBB)pathway is one of...Neurovascular dysfunction,as an integral part of Alzheimer's disease,may have an important influence on the onset and progression of chronic neurodegenerative processes.The bloodbrain barrier(BBB)pathway is one of the main pathways that mediates the clearance of amyloidbeta(Aβ)in the brain parenchyma.A large number of studies have shown that receptors and ATPbinding cassette transporte rs expressed on endothelial cells play an important role in Aβtransport across the BBB,but the specific mechanism is not clear.In this review,we summarize the possible mechanisms of Aβproduction and clearance,and in particular the relationship between Aβand brain capillary endothelial cells.Aβis produced by abnormal cleavage of the amyloid precursor protein via amyloidogenic processing under pathological conditions.Dys regulation of Aβclearance is considered to be the main reason for the massive accumulation of Aβin the brain parenchyma.Several pathways mediating Aβclearance from the brain into the periphery have been identified,including the BBB pathway,the blood-cerebros pinal fluid barrier and arachnoid granule pathway,and the lymphoidrelated pathway.Brain ca pilla ry endothelial cells are the key components of Aβclearance mediated by BBB.Receptors(such as LRP1,RAGE,and FcRn)and ATP-binding cassette transporters(such as P-gp,ABCA1,and ABCC1)expressed on endothelial cells play a critical role in Aβtranscytosis across the BBB.The toxic effects of Aβcan induce dysregulation of receptor and transpo rter expression on endothelial cells.Excessive Aβexerts potent detrimental cerebrovascular effects by promoting oxidative stress,inducing chronic inflammation,and impairing endothelial structure and functions.All of these are main causes for the reduction in Aβclearance across the BBB and the accumulation of Aβin the brain parenchyma.Therefo re,studies on the intera ctions between Aβand brain capillary endothelial cells,including their receptors and transporters,studies on inhibition of the toxic effects of Aβon endothelial cells,and studies on promoting the ability of endothelial cells to mediate Aβclearance may provide new therapeutic strategies for Aβclearance in Alzheimer's disease.展开更多
Rare earth elements have unique physical, magnetic, luminescent and catalytic properties. They have been successfully used as medicine and probes in luminescent resonance energy transfer (LRET) for bioassays, as well ...Rare earth elements have unique physical, magnetic, luminescent and catalytic properties. They have been successfully used as medicine and probes in luminescent resonance energy transfer (LRET) for bioassays, as well as reagents for diagnosis in magnetic resonance imaging (MRI). In this progress report, we will focus on recent progress on how rare earth amino complexes bind to DNA and change DNA structure, especially on DNA B-Z transition induced by rare earth amino acid complex and its potential impact on Alzheimer’s disease (AD).展开更多
Amyloid-beta peptide is the main component of amyloid plaques, which are found in Alzhei- mer＇s disease. The generation and deposition of amyloid-beta is one of the crucial factors for the onset and progression of Al...Amyloid-beta peptide is the main component of amyloid plaques, which are found in Alzhei- mer＇s disease. The generation and deposition of amyloid-beta is one of the crucial factors for the onset and progression of Alzheimer＇s disease. Lipid rafts are glycolipid-rich liquid domains of the plasma membrane, where certain types of protein tend to aggregate and intercalate. Lipid rafts are involved in the generation of amyloid-beta oligomers and the formation of amyloid-beta peptides. In this paper, we review the mechanism by which lipid rafts disturb the aberrant deg- radative autophagic-lysosomal pathway of amyloid-beta, which plays an important role in the pathological process of Alzheimer＇s disease. Moreover, we describe this mechanism from the view of the Two-system Theory of fasciology and thus, suggest that lipid rafts may be a new target of Alzheimer＇s disease treatment.展开更多
基金financially supported by the National Natural Science Foundation of China,No.81473201the Natural Science Foundation of Educational Commission of Guizhou Province of China,No.2010043+1 种基金the Science and Technology Foundation of Guizhou Province of China,No.JZ[2014]2016the Modernization of Traditional Chinese Medicine Project of Guizhou Province of China,No.[2011]5086
文摘Dendrobium nobile Lindl.alkaloids（DNLA）,the active ingredients of a traditional Chinese medicine Dendrobium,have been shown to have anti-oxidative effects,anti-inflammatory action,and protective effect on neurons against oxygen-glucose deprivation.However,it is not clear whether DNLA reduces amyloid-beta（Aβ）-induced neuronal injury.In this study,cortical neurons were treated with DNLA at different concentrations（0.025,0.25,and 2.5 mg/L）for 24 hours,followed by administration of Aβ（25-35）（10μM）.Aβ（25-35） treatments increased cell injury as determined by the leakage of lactate dehydrogenase,which was accompanied by chromatin condensation and mitochondrial tumefaction.The damage caused by Aβ（25-35） on these cellular properties was markedly attenuated when cells were pretreated with DNLA.Treatment with Aβ（25-35）down-regulated the expressions of postsynaptic density-95 mRNA and decreased the protein expression of synaptophysin and postsynaptic density-95,all changes were significantly reduced by pretreatment of cells with DNLA.These findings suggest that DNLA reduces the cytotoxicity induced by Aβ（25-35） in rat primary cultured neurons.The protective mechanism that DNLA confers on the synaptic integrity of cultured neurons might be mediated,at least in part,through the upregulation of neurogenesis related proteins synaptophysin and postsynaptic density-95.
基金funded by the National Centre for the Replacement Refinement&Reduction of Animals in Research(NC3R:Grant#NC/L001152/1)the Macular Society,UK,National Eye Research Centrethe Gift of Sight Appeal
文摘e-related macular degeneration （AMD） causes irreversible loss of central vision for which there is no effective treatment. Incipient pathology is thought to occur in the retina for many years before AMD manifests from midlife onwards to affect a large proportion of the elderly. Although genetic as well as non-genetic/environmental risks are recognized, its complex aetiology makes it difficult to identify susceptibility, or indeed what type of AMD develops or how quickly it progresses in different individuals. Here we summarize the literature describing how the Alzheimer＇s-linked amyloid beta （Aβ） group of misfolding proteins accumulate in the retina. The discovery of this key driver of Alzheimer＇s disease in the senescent retina was unexpected and surprising, enabling an altogether different perspective of AMD. We argue that Aβ fundamentally differs from other substances which accumulate in the ageing retina, and discuss our latest findings from a mouse model in which physiological amounts of Aβ were subretinally-injected to recapitulate salient features of early AMD within a short period. Our discoveries as well as those of others suggest the pattern of Aβ accumulation and pathology in donor aged/AMD tissues are closely reproduced in mice, including late-stage AMD phenotypes, which makes them highly attractive to study dynamic aspects of Aβ-mediated retinopathy. Furthermore, we discuss our findings revealing how Aβ behaves at single-cell resolution, and consider the long-term implications for neuroretinal function. We propose Aβ as a key element in switching to a diseased retinal phenotype, which is now being used as a biomarker for latestage AMD.
基金supported in part by the Japan Society for the Promotion of Science(JSPS)Grant-in-Aid for Scientific Research,No.17K11813(to LX)Tai Shan Industrial Experts Program of China No.TSCY20170233(to FL)。
文摘As an aging-associated degenerative disease,Alzheimer’s disease is characterized by the deposition of amyloid beta(Aβ),oxidative stress,inflammation,dysfunction and loss of cholinergic neurons.Colla Corii Asini(CCA)is a traditional Chinese medicine which has been used for feebleness-related diseases and anti-aging.CCA might delay aging-induced degenerative changes in neurons.In the present study,we evaluated antioxidant activity,cytoprotective effects,and Aβremovability of enzyme-digested Colla Corii Asini(CCAD).Oxygen radical absorbance capacity(ORAC)activity assay showed that,as compared to gelatins from the skin of porcine,bovine and cold water fish,CCA exhibited the highest ORAC activity.The ORAC activity of CCA and CCAD was increased gradually by the length of time in storage.Ultrastructure analysis by scanning electron microscopy showed that among CCA manufactured in 2008,2013,2017 and gelatin from cold water fish skin,CCA manufactured in 2008 presented the smoothest surface structure.We further tested the protective effects of CCAD(manufactured in 2008)and enzyme-digested gelatin from cold water fish skin(FGD)on hydrogen peroxide(H2O2)-induced cell death in nerve growth factor-differentiated neuronal-like PC12 cells.Presto blue assay showed that both FGD and CCAD at 0.5 mg/m L increased cell viability in H2O2-treated neuronal-like PC12 cells.The protection of CCAD was significantly superior to that of FGD.Acetylcholinesterase(Ach E)assay showed that both FGD and CCAD inhibited Ach E activity in nerve growth factor-differentiated neuronal-like PC12 cells to 89.1%and 74.5%of that in non-treated cells,respectively.The data suggest that CCAD might be able to increase the neurotransmitter acetylcholine.Although CCAD inhibited Ach E activity in neuronal-like PC12 cells,CCAD prevented H2O2-induced abnormal deterioration of Ach E.ELISA and neprilysin activity assay results indicated that CCAD reduced amyloid beta accumulation and increased neprilysin activity in Aβ1–42-treated neuronal-like PC12 cells,suggesting that CCAD can enhance Aβclearance.Our results suggest that CCA might be useful for preventing and treating Alzheimer’s disease.
基金financially supported by the National Natural Science Foundation of China,No.81573771the Natural Science Foundation of Jiangsu Province of China,No.BK20151599
文摘Mounting evidence indicates that amyloid β protein（Aβ） exerts neurotoxicity by disrupting the blood-brain barrier（BBB） in Alzheimer＇s disease. Hyperoside has neuroprotective effects both in vitro and in vivo against Aβ. Our previous study found that hyperoside suppressed Aβ1-42-induced leakage of the BBB, however, the mechanism remains unclear. In this study, bEnd.3 cells were pretreated with 50, 200, or 500 μM hyperoside for 2 hours, and then exposed to Aβ1-42 for 24 hours. Cell viability was determined using 3-（4,5-dimethyl-2-thiazolyl）-2,5-diphenyl-2-H-tetrazolium bromide assay. Flow cytometry and terminal deoxynucleotidyl transferase-mediated d UTP nick-end labeling assay were used to analyze cell apoptosis. Western blot assay was carried out to analyze expression levels of Bax, Bcl-2, cytochrome c, caspase-3, caspse-8, caspase-9, caspase-12, occludin, claudin-5, zonula occludens-1, matrix metalloproteinase-2（MMP-2）, and MMP-9. Exposure to Aβ1-42 alone remarkably induced bEnd.3 cell apoptosis; increased ratios of cleaved caspase-9/caspase-9, Bax/Bcl-2, cleav ed caspase-8/caspase-8, and cleaved caspase-12/caspase-12; increased expression of cytochrome c and activity of caspase-3; diminished levels of zonula occludens-1, claudin-5, and occludin; and increased levels of MMP-2 and MMP-9. However, hyperoside pretreatment reversed these changes in a dose-dependent manner. Our findings confirm that hyperoside alleviates fibrillar Aβ1-42-induced BBB disruption, thus offering a feasible therapeutic application in Alzheimer＇s disease.
基金supported by the National Natural Science Foundation of China,No.31670832,31470807,31270872a grant from the National Key Research and Development Program of China,No.2016YFA0500301a grant from the State Key Laboratory of Protein and Plant Gene Research,College of Life Sciences,Peking University,China
文摘Previous studies have shown that sirtuin 1（SIRT1） reduces the production of neuronal amyloid beta（Aβ） and inhibits the inflammatory response of glial cells, thereby generating a neuroprotective effect against Aβ neurotoxicity in animal models of Alzheimer＇s disease. However, the protective effect of SIRT1 on astrocytes is still under investigation. This study established a time point model for the clearance of Aβ in primary astrocytes. Results showed that 12 hours of culture was sufficient for endocytosis of oligomeric Aβ, and 36 hours sufficient for effective degradation. Immunofluorescence demonstrated that Aβ degradation in primary astrocytes relies on lysosome function. Enzymatic agonists or SIRT1 inhibitors were used to stimulate cells over a concentration gradient. Aβ was co-cultured for 36 hours in medium. Western blot assay results under different conditions revealed that SIRT1 relies on its deacetylase activity to promote intracellular Aβ degradation. The experiment further screened SIRT1 using quantitative proteomics to investigate downstream, differentially expressed proteins in the Aβ degradation pathway and selected the ones related to enzyme activity of SIRT1. Most of the differentially expressed proteins detected are close to the primary astrocyte lysosomal pathway. Immunofluorescence staining demonstrated that SIRT1 relies on its deacetylase activity to upregulate lysosome number in primary astrocytes. Taken together, these findings confirm that SIRT1 relies on its deacetylase activity to upregulate lysosome number, thereby facilitating oligomeric Aβ degradation in primary astrocytes.
基金supported by grants from Hebei Provincial Science and Technology Bureau,No.08276101D-21
文摘Scutellaria baicalensis stem-leaf total flavonoid might attenuate learning/memory impairment and neuronal loss in rats induced by amyloid beta-peptide. This study aimed to explore the effects of Scutellaria baicalensis stem-leaf total flavonoid on amyloid beta-peptide-induced neuronal apoptosis and the expression of apoptosis-related proteins in the rat hippocampus. Male Wistar rats were given intragastric administration of Scutellaria baicalensis stem-leaf total flavonoid, 50 or 100 mg/kg, once per day. On day 8 after administration, 10 pg amyloid beta-peptide （25-35） was injected into the bilateral hippocampus of rats to induce neuronal apoptosis. On day 20, hippocampal tissue was harvested and probed with the terminal deoxyribonucleotidyl transferase-mediated biotin-16-dUTP nick-end labeling assay. Scutellaria baicalensis stem-leaf total flavonoid at 50 and 100 mg/kg reduced neuronal apoptosis induced by amyloid beta-peptide （25-35） in the rat hippocampus. Immunohistochemistry and western blot assay revealed that expression of the pro-apoptotic protein Bax, cytochrome c and caspase-3 was significantly diminished by 50 and 100 mg/kg Scutellaria baicalensis stem-leaf total flavonoid, while expression of the anti-apoptotic protein Bcl-2 was increased. Moreover, 100 mg/kg Scutellana baicalensis stem-leaf total flavonoid had a more dramatic effect than the lower dosage. These experimental findings indicate that Scutellaria baicalensis stem-leaf total flavonoid dose-dependently attenuates neuronal apoptosis induced by amyloid beta-peptide in the hippocampus, and it might mediate this by regulating the expression of Bax, cytochrome c, caspase-3 and Bcl-2.
基金Supported by the National Natural Science Foundation of China(No.81430009No.81400424)the Science and Technology Research and Development Project of Shaanxi Province(No.2014K11-03-07-04)
文摘AIM：To identify the pathological role of amyloid beta（Aβ） deposition in retinal degeneration,and explore Aβ deposition on the retinal pigment epithelium cells（RPE） layer and the associated structural and functional changes in Alzheimer＇s disease transgenic mice.METHODS：RPE changes in the eyes of APPswe/PS1 transgenic and none transgenic（NTG） mice over 20 months old were examined.Histological changes were investigated via hematoxylin and eosin（H＆E） staining and transmission electron microscopy（TEM） examination,whereas the expression of amyloid precursor protein（APP）,Aβ,Zonula occludens-1（ZO-1） and Ionized calcium binding adaptor molecule-1（IBA-1） were investigated using immunohistochemistry and immunofluorescence techniques.All of the obtained results were quantitatively and statistically analyzed.RESULTS：In aged transgenic mice,an APP-positive immunoreaction and Aβ deposition were detected on the RPE layer but were undetectable in NTG mice.The RPE demonstrated some vacuole changes,shortened basal infoldings and basal deposition in histopathological examination and TEM tests,wherein irregular shapes were indicated by ZO-1 disorganization through fluorescence.Furthermore,IBA-1 positive cells were observed to have accumulated and infiltrated into the RPE layer and localized beneath the RPE/Bruch＇s membrane（Br M） complex,which was accompanied by an increase in BrM thickness in aged transgenic mice in comparison to NTG mice.The IBA-1 positive cells were found to be co-stained with Aβ deposition on the RPE flat mounts.CONCLUSION：The observed Aβ deposition in the RPE layer may cause RPE dysfunction,which is associated with microglia cells infiltration into the retina of aged transgenic mice,suggesting that Aβ deposition probably plays a significant role in RPE-related degenerative disease.
基金supported by a grant under Key Projects of Guangxi Traditional Chinese Medical University, No.ZD2007041
文摘Telencephalin is a neural glycoprotein that reduces apoptosis induced by amyloid beta protein in the human neural tumor cell line PAJU. In this study, we examined the role of the ezrin/radixin/moesin protein family/phosphatidylinositol-3-kinase/protein kinase B pathway in this process. Western blot analysis demonstrated that telencephalin, phosphorylated ezrin/radixin/moesin and phosphatidylinositol-3-kinase/protein kinase B were not expressed in PAJU cells transfected with empty plasmid, while they were expressed in PAJU cells transfected with a telencephalin expression plasmid. After treatment with 1.0 nM amyloid beta protein 42, expression of telencephalin and phosphorylated phosphatidylinositol-3-kinase/protein kinase B in the transfected cells gradually diminished, while levels of phosphorylated ezrin/radixin/moesin increased. In addition, the high levels of telencephalin, phosphorylated ezrin/radixin/moesin and phosphatidylinositol-3-kinase/protein kinase B expression in PAJU cells transfected with a telencephalin expression plasmid could be suppressed by the phosphatidylinositol-3-kinase inhibitor LY294002. These findings indicate that telencephalin activates the ezrin/radixin/moesin family/phosphatidylinositol-3-kinase/protein kinase B pathway and protects PAJU cells from amyloid beta protein-induced apoptosis.
文摘Targeting early steps in amyloid-beta production：Alzheimer’s disease（AD）has a long history as the＂amyloid deposit＂disorder.Many disorders are now known to be caused by proteinβ-sheet misfolding and aggregation（e.g.,Parkinson’s disease：α-synuclein;Huntington’s disease：Huntingtin;
文摘BACKGROUND： The findings about the alterations in cerebrospinal fluid beta-amyloid protein （Aβ ） and apolipoprotein E （APOE） after subarachnoid hemorrhage indicate that they have significant correlation with prognosis of patients. OBJECTⅣE： To observe the alterations in cerebrospinal fluid Aβ and ApoE after subarachnoid hemorrhage （SAH）. DESIGN： Contrast observation. SETTING： Department of Neurosurgery, the First Hospital of Lanzhou University. PARTICIPANTS： A total of 25 SAH patients including 16 males and 9 females aged from 13 to 72 years were selected form Department of Neurosurgery, the First Affiliated Hospital of Lanzhou University from October 2003 to February 2004. The Hunt-Hess grade ranged from Ⅰ to Ⅳ, and patients admitted hospital in 24 hours after invasion, affirmed by the brain CT scan and lumbar vertebra puncture, no other severe complications and important organs＇ functional defect and severe infection, no hematological system disease. METHODS- All admitted patients were collected CSF by lumbar vertebra puncture in 24 hours. The cerebrospinal fluid （CSF） of control group came from the admitted 15 patients of our hospital that have no nervous system disease. Aβ content was detected by enzyme linked immunosorbent assay （ELISA）, the kit was provided by the Central Laboratory of the First Hospital of Lanzhou University; ApoE concentration was detected by monoclone enzyme linked immunosorbent assay （ELISA）, the kit was provided by the Immunotechnique Research Institute of the Fourth Military Medical University. S100B concentration was detected by enzyme linked immunosorbent assay double antibody sandwich method, the kit was provided by the Physiological Research Room of the Fourth Military Medical University. The data were indicated on Mean±SD and were analyzed by SPSS 10.0 statistical package. All data were handled through test of significance variance analysis, and groups were compared through independent sampler t test. The concentration was handled through Pearson correlation analysis between Aβ and ApoE. The relationship between Aβ, ApoE concentration with pathogenetic condition and prognosis of the patients was handled through Spearman ranking correlation analysis. MAIN OUTCOME MEASURES：① The concentration of ApoE, Aβ and S100B after SAH in contrast to the control group in CSF by different Hunt-Hess and Glasgow Outcome Scale （GOS） grades; ② The level of correlation between ApoE and Aβ ; ③Correlation between ApoE and Aβ in pathogenetic condition and prognosis of the patients. RESULTS： All 25 SAH patients and 15 controls were involved in the final analysis. ① The concentration of ApoE, Aβ and S100B in CSF： The concentration of ApoE decreased after SAH in contrast to the control group [（0.46±0.007）, （0.85±0.11） μg/L, P 〈 0.01], the concentration of ApoE decreased after SAH in contrast to the control group [（5.36± 1.19）, （8.41± 1.60） μg/L, P 〈 0.01], and the concentration of S100B increased after SAH in contrast to the control group [（18.60±7.31）, （6.56±1.02） pg/L, P 〈 0.01]. ② The concentration of ApoE, Aβ and S100B in CSF after SAH on different Hunt-Hess and GOS grades： The concentration of Aβ in Hunt-Hess Ⅰ -Ⅲ grade was higher than Hunt-Hess Ⅳ, Ⅴ grade [（6.63 ± 1.25）, （3.35± 1.02） μg/L, P 〈 0.01], and the concentration of ApoE in Hunt-Hess Ⅰ- Ⅲ grade was higher than Hunt-Hess Ⅳ, Ⅴ grade [（0.56±0.07）, （0.38±0.04） μg/L, P 〈 0.05], the concentration of S100B in Hunt-Hess Ⅰ - Ⅲ grade was lower than Hunt-Hess Ⅳ - Ⅴ grade [（16.32±5.58）, （22.85±8.10） pg/L, P 〈 0.01]; the concentration of Aβ in GOS Ⅰ - Ⅲ grade was lower than GOS Ⅳ, Ⅴ grade [（3.76± 1.04）, （5.89±1.20） μg/L, P 〈 0.01], and the concentration of ApoE in GOS Ⅰ - Ⅲ grade was lower than GOS Ⅳ, Ⅴ grade [（0.32±0.02）, （0.58±0.07） μg/L, P 〈 0.011, and the concentration of S100B in GOS Ⅰ - Ⅲ grade was higher than GOS Ⅳ, Ⅴ grade [（25.36±9.70）, （14.33±6.69） pg/L, P 〈 0.01].③ The results of Pearson correlation analysis and Spearman ranking correlation analysis： There was significantly positive correlation between CSF Aβ concentration and clinical outcome （r=0.65, P 〈 0.01）, and the decrease in CSF Aβ concentration correlated significant with that of ApoE （r =0.85, P 〈 0.01）. CONCLUSION： There is a significant decrease in both Aβ and ApoE in the CSF after SAH, and there is significant correlation between CSF Aβ and ApoE concentration with clinical outcome, the interactions between these proteins may have important effects on SAH, ApoE and Aβ as surrogate markers for the outcome of patients with SAH.
文摘Alzheimer’s disease（AD）is the most common form of age-related dementia with the latest report（World Alzheimer Report,2015）showing 46.8 million people are currently affected by dementia.That number is expected to double every 20 years unless there is effective therapeutic intervention.The 42 amino acid peptide known as amyloid beta（or Aβ）has been implicated as one of the main causative agents of AD after its discovery in plaques in 1985（Masters et al.,1985）.
文摘Recent studies have demonstrated that Notch-1 expression is increased in the hippocampus of Alzheimer＇s disease patients. We speculate that Notch-1 signaling may be involved in PC12 cell apoptosis induced by amyloid beta-peptide （25-35） （Aβ25-35）. In the present study, PC12 cells were cultured with different doses （0, 0.1, 1.0, 10 and 100 nmol/L） of N-[N-（3,5-Difluorophenacetyl）-L-alanyl]-S-phenylglycine t-butyl ester, a Notch-1 signaling pathway inhibitor, for 30 minutes. Then cultured cells were induced with Aβ25-3s for 48 hours. Pretreatment of PC12 cells with high doses of N-[N-（3,5-Difluorophenacetyl）-L-alanyl]-S-phenylglycine t-butyl ester （〉 10 nmol/L） prolonged the survival of PC12 cells after Aβ25-35 induction, decreased the expression of apoptosis-related proteins caspase-3, -8, -9, increased the activity of oxidative stress-related superoxide dismutase and catalase, inhibited the production of active oxygen, and reduced nuclear factor kappa B expression. This study indicates that the Notch-1 signaling pathway plays a pivotal role in Aβ25-35-induced PC12 apoptosis.
基金Guha S wishes to thank UR PDA Career Enhancement Award 2020 for covering the subscription fee of bio-render and other bureaucratic cost.Subramaniyam R wishes to thank DST-inspire program for the research grant(No.DST/INSPIRE/04/2015/001945).
文摘Alzheimer’s disease(AD)is the most common progressive neurodegenerative disorder.It is often lethal and currently lacks a satisfactory therapy.The disease has a specific neuro-pathological profile:accumulation of proteinaceous deposits in the brain–amyloid plaques(containingβ-amyloid peptides)and neurofibrillary tangles which are accumulation of a profusion of long stringy tangles of proteins called tau.Between the two highly recognized AD hypotheses,amyloid beta(Aβ)peptide aggregation and accumulation play a significant role and are considered as an important mechanism of AD pathology.Aβis a proteolytic product of amyloid precursor protein and genetic studies supported the relevance of Aβin AD pathogenesis.A large number of small molecules were studied for their ability to inhibit Aβ-aggregation in oligomer form or after fibrillization.However,the protein-misfolding process has certain setbacks which are inevitable due to the different morphology of protein.In recent years,it has been demonstrated that tau also plays a central role in pathogenesis of this disease.Moreover,abnormal post-translational modifications of tau,in particular,increases in acetylation at specific sites likely contribute to the toxicity of tau.Although it is evident that tau with these aberrant post-translational modifications likely facilitates neurodegeneration,the precise cellular mechanisms by which tau compromises neuronal function remain unknown.In addition,much remains to be learned about new interventions that might be developed to prevent or reduce the negative impact of tau posttranslational modifications-related damage.This review article addresses the key roles of amyloid beta and tau protein in AD as well as the possible therapeutic agents that can reduce the toxic levels of both the proteins,and thus providing beneficial effect for the AD patients.
基金supported by the Natural Science Foundation of Shandong Province of China,No.ZR2014HM046(to ZCZ)
文摘Amyloid beta（Aβ）-induced oxidative stress is a major pathologic hallmark of Alzheimer＇s disease. Cyanidin, a natural flavonoid compound, is neuroprotective against oxidative damage-mediated degeneration. However, its molecular mechanism remains unclear. Here, we investigated the effects of cyanidin pretreatment against Aβ-induced neurotoxicity in PC12 cells, and explored the underlying mechanisms. Cyanidin pretreatment significantly attenuated Aβ-induced cell mortality and morphological changes in PC12 cells. Mechanistically, cyanidin effectively blocked apoptosis induced by Aβ, by restoring the mitochondrial membrane potential via upregulation of Bcl-2 protein expression. Moreover, cyanidin markedly protected PC12 cells from Aβ-induced DNA damage by blocking reactive oxide species and superoxide accumulation. These results provide evidence that cyanidin suppresses Aβ-induced cytotoxicity, by preventing oxidative damage mediated by reactive oxide species, which in turn inhibits mitochondrial apoptosis. Our study demonstrates the therapeutic potential of cyanidin in the prevention of oxidative stress-mediated Aβ neurotoxicity.
文摘An important marker in neurodegenerative Alzheimer’s disease (AD) is abnormal production of amyloid beta (Aβ) peptide leading to formation of plaques in the brain. Through decreasing Aβ aggregates, anti-inflammatory agents, phagocytosis, and proteolytic enzymes are known to decline risk of Aβ plaque formation. In the previous study we showed that aqueous extract of Lavandula angustifolia (lavender), with known anti-inflammatory effects, improves memory deficits in animal model of Alzheimer. Here, we assess if lavender play a role in clearance of Aβ plaques in the hippocampus. The Alzheimeric animals were created with intracerebroventricular injection of Aβ 1-42. To confirm formation of Aβ plaques, brain sections were stained by Congo red method. Twenty days post-injection they were administered with different doses (50, 100 and 200 mg/kg) of the aqueous extract of lavender for duration of 20 days. Our results demonstrated that 50 mg/kg of lavender not effectively influenced the Aβ plaques. On the other hand, the herbal medicine at the doses of 100 and 200 mg/kg markedly decreased the extent of Aβ aggregates. We concluded that the lavender extract dose dependently underlies elimination of Aβ plaques. The exact mechanism by which the herbal medicine removes the Aβ aggregates needs to be elucidated.
基金Shanxi Provincial Special Fund for the Transformation of Scientific and Technological Achievements,No.201704D13111584(to JHG)。
文摘Neurovascular dysfunction,as an integral part of Alzheimer's disease,may have an important influence on the onset and progression of chronic neurodegenerative processes.The bloodbrain barrier(BBB)pathway is one of the main pathways that mediates the clearance of amyloidbeta(Aβ)in the brain parenchyma.A large number of studies have shown that receptors and ATPbinding cassette transporte rs expressed on endothelial cells play an important role in Aβtransport across the BBB,but the specific mechanism is not clear.In this review,we summarize the possible mechanisms of Aβproduction and clearance,and in particular the relationship between Aβand brain capillary endothelial cells.Aβis produced by abnormal cleavage of the amyloid precursor protein via amyloidogenic processing under pathological conditions.Dys regulation of Aβclearance is considered to be the main reason for the massive accumulation of Aβin the brain parenchyma.Several pathways mediating Aβclearance from the brain into the periphery have been identified,including the BBB pathway,the blood-cerebros pinal fluid barrier and arachnoid granule pathway,and the lymphoidrelated pathway.Brain ca pilla ry endothelial cells are the key components of Aβclearance mediated by BBB.Receptors(such as LRP1,RAGE,and FcRn)and ATP-binding cassette transporters(such as P-gp,ABCA1,and ABCC1)expressed on endothelial cells play a critical role in Aβtranscytosis across the BBB.The toxic effects of Aβcan induce dysregulation of receptor and transpo rter expression on endothelial cells.Excessive Aβexerts potent detrimental cerebrovascular effects by promoting oxidative stress,inducing chronic inflammation,and impairing endothelial structure and functions.All of these are main causes for the reduction in Aβclearance across the BBB and the accumulation of Aβin the brain parenchyma.Therefo re,studies on the intera ctions between Aβand brain capillary endothelial cells,including their receptors and transporters,studies on inhibition of the toxic effects of Aβon endothelial cells,and studies on promoting the ability of endothelial cells to mediate Aβclearance may provide new therapeutic strategies for Aβclearance in Alzheimer's disease.
基金Project supported by the NSFC (20831003, 90813001, 20903086)Funds from CAS
文摘Rare earth elements have unique physical, magnetic, luminescent and catalytic properties. They have been successfully used as medicine and probes in luminescent resonance energy transfer (LRET) for bioassays, as well as reagents for diagnosis in magnetic resonance imaging (MRI). In this progress report, we will focus on recent progress on how rare earth amino complexes bind to DNA and change DNA structure, especially on DNA B-Z transition induced by rare earth amino acid complex and its potential impact on Alzheimer’s disease (AD).
基金supported by a grant from Projects of High-tech Industrialization of Guangdong Province of China,No.2011B010500004a grant from National Financial Major Project of China
文摘Amyloid-beta peptide is the main component of amyloid plaques, which are found in Alzhei- mer＇s disease. The generation and deposition of amyloid-beta is one of the crucial factors for the onset and progression of Alzheimer＇s disease. Lipid rafts are glycolipid-rich liquid domains of the plasma membrane, where certain types of protein tend to aggregate and intercalate. Lipid rafts are involved in the generation of amyloid-beta oligomers and the formation of amyloid-beta peptides. In this paper, we review the mechanism by which lipid rafts disturb the aberrant deg- radative autophagic-lysosomal pathway of amyloid-beta, which plays an important role in the pathological process of Alzheimer＇s disease. Moreover, we describe this mechanism from the view of the Two-system Theory of fasciology and thus, suggest that lipid rafts may be a new target of Alzheimer＇s disease treatment.
