Icariin decreases neuro-pathogenesis and improves learning and memory functions in Tg2576 mice

Alzheimer′s disease(AD) is one of the most common neurodegenerative diseases,showing progressive memory and cognitive deficits.The predominant neuropathological features of AD are extracellular senile plaques(SP) composed by over expression of amyloid beta protein(Aβ),hyperphosphorylation of Tau protein forming the neurofibrillary tangles(NFTs) and neuronal loss in the specific brain subregions.However,the cause of dementia of AD are still not known,the neurotoxicity of over expressed Aβ coming from the proteolysis of amyloid precursor protein(APP) may play a important role.Aβ neurotoxicity has been widely reported in vitro and in vivo,including the impairment of long term potentiation(LTP),disruption of synaptic plasticity.Aβ also triggered neuron inflammation,and disturbed neurogenesis.caused neuronal oxidative damage and apoptosis,eventually resulted in memory loss At this moment,there are no effective pharmacologic interventions that could halt the progression of AD.Current pharmacotherapies,such as acetylcholinesterase inhibitors including donepezil,rivastigmine and galantamine,and a NMDA antagonist,memantine,improve symptoms but do not block the disease progression.New strategies to slow and/or reverse the pathogenesis of patients with AD are greatly needed.Traditional Chinese Medicine such as icariin may provide an unique opportunity for seeking more safe and effective therapies for AD.In this study we were examine the protective effect of icariin on Tg2576 mice,a well established animal model of AD.Our results demonstrated that chronic treatment of Tg2576 mice with icariin from age of 8 to 11 months,could improve the memory function of Tg2576 mice.In addition,icariin decreased the APP,Aβ levels,and amyloid plaque number in Tg2576 mouse brain.Finally,icariin promoted cell proliferation and differentiation into neuron in the dentate gyrus(DG) of hippocampus in aged Tg2576 mouse.Neurogenesis following icariin administration may due to the decrease of Aβ levels and phosphodiesterase type 5(PDE5),amelioration of the Aβ neurotoxicity,and increase of brain-derived neurotrophic factor(BDNF) expression in mouse brain.In summary,aged Tg2576 mice deministrated neuropathogenesis and cognitive deficits in thebrain,.Chronic treatment of icariin in Tg2576 mice significantly decreased the neuropathogenesis and improved cognitive function.Icariin stimulates neurogenesis in aged Tg2576 mice displayed further neuro-protection in aged brain.Our results provide solid evidence in support that icariin could be a potential compound for AD therapy.     

Expression of β-Amyloid Peptide at Different Time Points After Transient Focal Cerebral Ischemia in Rats

Background and Purpose： Previous studies have shown that one central issue in AD pathogenesis is the amyloid cascade hypothesis, and cerebral ischemia can provoke focal accumulation of β amyloid （Aβ）, while it is not clear that how about was the expression characteristic of Aβ after cerebral ischemia. In this experiment, we studied the expression characteristic of Aβ after cerebral ischemia. Methods： Rats were divided into two groups, normal-group, model -group.     

Beneficial Effects of （ - ）clausenamide in Experimental Models of Alzheimer＇s Disease

AIMS ： Alzheimer＇s disease （ AD）, which is neuropathologyically characterized by senile plaque composed of amyloid protein depositions,neurofibrillary tangle and neuron loss in central nervous system, is the most common disease occurred in aged people. （ - ） Clausenamide is a new compound isolated from Clausena Lansium Lour Skells, and its natural structure is similar to piracetam. In this study, our aims are to study the （ - ） clausenamide＇s pharmacological effects in various AD＇s pathological models.     

Stable expression of amloid protein precursor gene in SH-EP1 cells transfected with nicotinic acetylcholine receptor α4β2 subtype gene

Alzheimer＇s disease （AD） is one of the most common neurodegenerative diseases that affects the elderly. Neuropathologically, AD brains are characterized by the accumulation of extracellular amyloid plaques, mainly formed by a small peptide called amyloid-β （Aβ） .     

Disruption of estrogen receptor beta in mice brain results in pathological alterations resembling Alzheimer disease

AIM: To study the pathological characteristics of the mice with estrogen receptor β (ERβ) disruption in brain.METHODS: Immunohistochemistry method was applied in the study. RESULTS: β-Amyloid peptide(Aβ42) and apolipoprotein E (ApoE) immunoreactive substances were accumulated notably in cortex and limbic structures such as the hippocampus and amygdala in brain, resembling the pathological changes of human Alzheimer disease(AD). Aβ formed cloudy-like deposits in parenchyma of brain, while apoE also deposited along or surrounding the blood vessels. CONCLUSIONS: ERβ is crucial to the development of neural degenerative disease, so modulation of Aβ metabolism via ERβ signal pathway might be beneficial for AD prevention or therapy.     

Expression of PDCD5, a novel apoptosis related protein, in human osteoarthritic cartilage

INTRODUCTIONOsteoarthritis (OA) is a degenerative joint diseasecharacterized by the progressive erosion of articularcartilage as well as the thickening of subchondral bone[1].The pathogenesis of OA is poorly understood[2,3], how-ever it is believed that both an imbalance between carti-lage degradation and synthesis that leads to extracellularmatrix damage as well as a severe loss of chondrocytesin the articular cartilage participate in the process. Theloss of chondrocytes is at least pa…     

Clearance of beta- amyloid from the CSF by the choroid plexus： implications in drug development for treatment of Alzheimer＇s disease

The formation of insoluble aggregates of beta - amyloid peptide （ A ） within the brain extracellular fluid is a critical event in the etiology of Alzheimer＇s disease （AD）. In theory, an unbalanced A kinetics can be due to its over production, inadequate metabolic cleaning, or an improper balance of import or export of A or related molecules at brain barriers. We investigated the role of the choroid plexus, which forms a barrier between blood and brain cerebrospinal fluid （ CSF）, in regulating A in the CSF. A uptake from CSF was determined as its volume of distribution （ VD ） into isola- ted rat choroid plexus tissue by using [^125I] A 1-40 and along with a extracellular space marker [^14C ] sucrose. The choroid plexus exhibited a definite capacity in sequestering [^125I] A 1-40 from the surrounding CSF. Uptake of [^125I] A by the choroid plexus was saturable, time - and temperature - dependent, and not ttffected by addition of transthyretin or apolipoprotein E3. Studies with cultured monolayers of primary choroid epithelial cells indicated that A permeability across cells, corrected by [ ^14C] sucrose, was greater from the CSF -facing membrane than from the blood -facing membrane. Similarly, cellular accumulation of [ ^125 I ] A was concentrative from both directions and was greater from the CSF -facing membrane. Quantitative real- time RT- PCR, immunodetection and enzyme activity assays further revealed the presence of several key enzymes involved in A production, e. g. , amyloid precursor protein and beta - secretase, and in A metabolism and alternate processing, e. g. , insulin degrading enzyme, endothelin - converting enzyme - 1, neprilysin and alpha - secretase. Overall, these results suggest the choroid plexus selectively cleanses A from the CSF by an undetermined mechanism （s） ; moreover, it has the capacity to degrade A , suggesting a vital role of this tissue in maintaining A homeostasis. The perspectives of drug development for treatment of AD by reducing A from brain extracellular fluid as a new strategy will be discussed.     

Inhibitory effects of 1-methyl-4-phenylpyridinium on glutamate uptake into cultured C6 glioma cells

INTRODUCTION Glutamate is a predominant excitatory neurotrans-mitter in the mammalian central neuron system[1]. En-hanced glutamatergic activity is implicated in the pa-thology of neurological diseases, such as Parkinson dis-ease (PD)[1]. PDis characterized by a progressive andselective loss of dopaminergic neurons in substantianigra pars compacta (SNpc) which is the site of a glialactivation in PD. Regulation of glutamate level in thesynaptic cleft by glutamate transporters loca…     

Estrogen stimulates release of secreted amyloid precursor protein from primary rat cortical neurons via protein kinase C pathway

Aim: To investigate the mechanism of the action of estrogen, which stimulates the release of secreted amyloid precursor protein α (sAPPα) and decreases the generation of amyloid-β protein (Aβ), a dominant component in senile plaques in the brains of Alzheimer‘s disease patients. Methods: Experiments were carried out in primary rat cortical neurons, and Western blot was used to detect sAPPα in aculture medium and the total amount of cellular amyloid precursor protein (APP) in neurons. Results: 17β-Estradiol (but not 17α-estradiol) and β-estradiol 6-(0-carboxymethyl) oxime: BSA increased the secretion of sAPPα and this effect was blocked by protein kinase C (PKC) inhibitor caiphostin C, but not by the classical estrogen receptor antagonist ICI 182,780. Meanwhile, 17β-estradiol did not alter the synthesis of cellular APP. Conclusion: The effect of 17β-estradiol on sAPPα secretion is likely mediated through the membrane binding sites, and needs molecular configuration specificity of the ligand. Furthermore, the action of the PKCdependent pathway might be involved in estrogen-induced sAPPα secretion.     

Melatonin attenuates β-amyloid-induced inhibition of neurofilament expression

AIM: To explore the effect of β-amyloid (Aβ) on metabolism of cytoskeletal protein neurofilament, and search for effective cure to the lesion. METHODS: Wild type murine neuroblastoma N2a (N2awt) and N2a stably transfected with wild type amyloid precursor protein (N2aAPP) were cultured. Sandwich ELISA, immunocytochemistry, and Western blot were used respectively to measure the level of Aβ, the expression and phosphorylation of neurofilament proteins. RESULTS: The immunoreactivity of neurofilament protein was almost abolished in N2aAPP, which beard a significantly higher level of Aβ. Melatonin effectively decreased the level of Aβ, and restored partially the level of phosphorylated and non-phosphorylated neurofilament in N2aAPP. CONCLUSION: Overproduction of Aβ inhibits neurofilament expression, and melatonin attenuates the Aβ-induced lesion in cytoskeletal protein.     

APP modulator regulates amyloid precursor protein processing in vitro by increasing a-secretase activity： Therapeutic potential in Aizheimer＇s disease？

The beta amyloid cascade has been at the forefront of the hypothesis used to describe the pathogenesis of Alzheimer＇s disease （AD） . It is generally accepted that drugs that can regulate the processing of the amyloid precursor protein （APP） toward the non-amyloidogenic pathway may have a therapeutic potential in AD.     

Stable expression of amiloid protein precursor gene in SH- EPI cells transfected with nicotinic acetylcholine receptor α7 subtype gene

The senile plaques in the brain are thought to contribute to the pathogenesis of Alzheimer＇s disease （AD） and are mainly consisted of β - amyloid peptide, which is the proteolytic product of amyloid precursor protein （APP）. Previous work suggested that nicotine could effectively reduce β - amyloid peptide aggregation in the brain of animal models and improve the cognition impairment, indicating that the nicotinic acetylcholine receptors （nAChR） might play an important part in the function of memory and cognition and might be a target in the therapy of Alzheimer＇s disease. The α7 nicotinic acetylcholine receptors are highly expressed in hippocampus and in cholinergic neurons from the basal forebrain, structures that are particularly vulnerable to the ravages of Alzheimer＇s disease. To test whether the α7 nicotinic acetylcholine receptors can block the processing of amyloid precursor protein into β - amyloid peptide, we transfected human APP695 into the native nAChR - null SH - EP1 human epithelial cells which had been transfected with the gene of α7nAChR and confirmed their expression by RT - PCR and Western Blot.     

Icariside Ⅱ inhibits lipopolysaccharide-induced inflammation and amyloid production in rat astrocytes by regulating IKK/IκB/NF-κB/BACE1 signaling pathway

β-amyloid(Aβ)is one of the inducing factors of astrocytes activation and neuroinflammation,and it is also a crucial factor for the development of Alzheimer’s disease(AD).Icariside II(ICS II)is an active component isolated from a traditional Chinese herb Epimedium,which has shown to attnuate lipopolysaccharide(LPS)-induced neuroinflammation through regulation of NF-κB signaling pathway.In this study we investigated the effects of ICS II on LPS-induced astrocytes activation and Aβaccumulation.Primary rat astrocytes were pretreated with ICS II(5,10,and 20μM)or dexamethasone(DXMS,1μM)for 1 h,thereafter,treated with LPS for another 24 h.We found that ICS II pretreatment dose dependently mitigated the levels of tumor necrosis factor-alpha(TNF-α),interleukin-1 beta(IL-1β),inducible nitric oxide synthase(iNOS),cyclooxygenase-2(COX-2)in the astrocytes.Moreover,ICS II not only exerted the inhibitory effect on LPS-induced IκB-αdegradation and NF-κB activation,but also decreased the levels of Aβ1–40,Aβ1–42,amyloid precursor protein(APP)and beta secretase 1(BACE1)in the astrocytes.Interestingly,molecular docking revealed that ICS II might directly bind to BACE1.It is concluded that ICS II has potential value as a new therapeutic agent to treat neuroinflammation-related diseases,such as AD.     

Effects of Ginkgolide B on action potential and calcium, potassium current in guinea pig ventricular myocytes

INTRODUCTION Ginkgo biloba extract (GbE) is extracted fromthe leaves of Ginkgo biloba. GbE is a multicomponentdrug with a polyvalent action. In Germany and France,such extracts were used effectively to treat cerebraldysfunction and peripheral circulatory disturbances[1].The results of clinical trails support new indications forGbE in the treatment of cardiovascular disease, par-ticularly in the prevention of ischemic heart syndromes[2].The primary active constituents of GbE incl…     

Reduction of RhoC is involved in the decreased migration of neural stem/precursor cells

OBJECTIVE Alzheimer′s disease(AD) is mainly characterized by a progressive loss of neurons and the deposition of beta-amyloid peptides(Aβ).It was demonstrated that transplanted and endogenous neural stem cells or neural precursor cells can survive,migrate,and differentiate into neurons.Previously we found that Aβ42 could disturb the migratory ability of neural stem/precursor cells.We therefore hypothesized that Aβ42 may affect some important proteins through Rho pathway and result in the decreased migration of neural stem/precursor cells.METHODS AND RESULTS We applied siRNA technology to knock down the expression of RhoC in neural stem/precursor cells and found that the expression of RhoC was down-regulated;Trans well assay was used to measure the migratory ability of the neural stem/precursor cells and the result showed that the migratory ability was disturbed when the expression of RhoC was down-regulated;WRW4 was used for inhibiting the effects of the Aβ42 through the FPRL1.CONCLUSION The reduction of RhoC was involved in the decreased migration of neural stem cells.     

GSK3β regulates D1 dopamine receptor phosphorylation and function

Many protein kinases have been shown to regulate the phosphorylation of G - protein - coupled receptors. These kinases, together with associated protein phosphatases form complexes that regulate the function of G - protein - coupled receptors. In brain, protein phosphatasel （ PP1 ） exists as a complex with PP1 inhibitor - 2 （ I - 2）. Phosphorylation of I - 2 by cdk5 or GSK3β results in activation of PP1. The present study was designed to investigate the role of GSK3β in the regulation of D1 dopamine receptor function. In rat and rabbit frontal cortex （FCX）, we found that GSK3β co -precipitates with D1A dopamine receptor. Furthermore, GSK3w is physically associated with I -2, indicating that GSK3β/I -2/PP1/D1 receptor form a receptor - kinase - phosphatase complex. In prenatal cocaine - exposed rabbit, we reported a selective impairment of D1 dopamine receptor function in FCX that is the result of D1 receptor hyper - phosphorylation that is due to decreased PP1 activity. Interestingly, we detected a significant decrease in GSK3β activity in FCX of cocaine- exposed rabbits. Moreover, decreased association between GSK3β and I -2 was also observed, suggesting that GSK3β activity is nee ded for the association between these two molecules. Indeed, preincubation of GSK3β inhibitor 1 with FCX membranes induced a decrease in association between the kinase and I -2. In accord with the decrease in FCX GSK3β activity that is found in prenatal cocaine - exposed rabbit, PP1 activity, and specifically, Dt receptor - associated PP1 activity, was also decreased. Taken together, the present results indicate that GSK3β forms a complex with Dt dopamine receptor, PP1 and I - 2 that regulates D1 receptor function via modulation of PP1 activity. Inhibition of GSK3β activity, as is the case in prenatal cocaine - exposed brain, results in reduced PP1 activity and hyper - phosphorylation of the D1 dopamine receptor and ultimately leads to the dysfunction of the D1 receptor. In addition, in HEK293 cell line stably expressing D1 receptor,     

Recombinant fibronectin polypeptide antagonizes hepatic failure induced by endotoxin in mice

INTRODUCTION Fibronectin (FN) is known to be a large multifunc-tional glycoprotein with binding sites for many sub-stances and integrin cell-surface receptors on a varietyof cells including fibroblasts, phagocytes and bacte-ria[1]. Extensive in vitro functional analyses indicatethat FN modulates cell proliferation, migration and sur-vival[2]. FN interacts with cells in cell-binding domainswith RGDS sequence, which is located in the 10th typeIII repeats of FN, the synergy seque…