黄连解毒汤对APP/PS1双转基因阿尔茨海默病模型小鼠脑组织的保护

Huanglian Jiedu decoction(HLJDD) has been shown to improve cerebral blood flow,and reduce lipid peroxidation damage to the brain and its energy metabolism.The present study was designed to observe the cerebroprotective effect of HLJDD on an Alzheimer’s disease rodent model,prese-nilin-1/amyloid protein precursor double transgenic mice.HLJDD reduced serum interleukin-6 and interleukin-1β levels,decreased β-amyloid precursor protein gene and senile plaque expression,resisted oxidation,and reduced free radical-induced injury,thereby improving the learning and memory of these mice.Moreover,HLJDD at 433 mg/kg per day exhibited better effects compared with that at 865 or 216 mg/kg per day,and donepezil hydrochloride at 30 mg/kg per day.Thus,these results suggest that HLJDD may have protective effects against Alzheimer’s disease.     

Estrogen receptor beta treats Alzheimer’s disease

In vitro studies have shown that estrogen receptor β can attenuate the cytotoxic effect of amyloid β protein on PC12 cells through the Akt pathway without estrogen stimulation. In this study, we aimed to observe the effect of estrogen receptor β in Alzheimer’s disease rat models established by intraventricular injection of amyloid β protein. Estrogen receptor β lentiviral particles delivered via intraventricular injection increased Akt content in the hippocampus, decreased interleukin-1β mRNA, tumor necrosis factor α mRNA and amyloid β protein levels in the hippocampus, and improved the learning and memory capacities in Alzheimer’s disease rats. Estrogen receptor β short hairpin RNA lentiviral particles delivered via intraventricular injection had none of the above impacts on Alzheimer’s disease rats. These experimental findings indicate that estrogen receptor β, independent from estrogen, can reduce inflammatory reactions and amyloid β deposition in the hippocampus of Alzheimer’s disease rats, and improve learning and memory capacities. This effect may be mediated through activation of the Akt pathway.     

Presenilin mutations and their impact on neuronal differentiation in Alzheimer’s disease

The presenilin genes(PSEN1 and PSEN2)are mainly responsible for causing early-onset familial Alzheimer’s disease,harboring~300 causative mutations,and representing~90%of all mutations associated with a very aggressive disease form.Presenilin 1 is the catalytic core of theγ-secretase complex that conducts the intramembranous proteolytic excision of multiple transmembrane proteins like the amyloid precursor protein,Notch-1,N-and E-cadherin,LRP,Syndecan,Delta,Jagged,CD44,ErbB4,and Nectin1a.Presenilin 1 plays an essential role in neural progenitor maintenance,neurogenesis,neurite outgrowth,synaptic function,neuronal function,myelination,and plasticity.Therefore,an imbalance caused by mutations in presenilin 1/γ-secretase might cause aberrant signaling,synaptic dysfunction,memory impairment,and increased Aβ42/Aβ40 ratio,contributing to neurodegeneration during the initial stages of Alzheimer’s disease pathogenesis.This review focuses on the neuronal differentiation dysregulation mediated by PSEN1 mutations in Alzheimer’s disease.Furthermore,we emphasize the importance of Alzheimer’s disease-induced pluripotent stem cells models in analyzing PSEN1 mutations implication over the early stages of the Alzheimer’s disease pathogenesis throughout neuronal differentiation impairment.     

Neurotrophin receptors,gamma-secretase inhibitors,and neurodegeneration of basal forebrain cholinergic neurons

The amyloid hypothesis of Alzhemer’s disease(AD)postulates that the generation of amyloid-beta(Aβ)peptide from the amyloid precursor protein(APP)by the action of theγ-secretase complex is one of the principal causes of AD.This idea is supported by the identification of several hereditary mutations in the APP gene or in the PSEN1 and PSEN2 genes that encode Presenilin-1 and Presenilin-2.     

Wnt-5a对Aβ引起大鼠记忆功能损害的保护途径

Recent studies suggest that the activation of the Wnt signaling pathway improves memory function in rats.This study investigated the effects of Wnt-5a on amyloid β (Aβ)-induced cognitive impairment.Aβ25-35 was injected into the rat right lateral ventricle to induce Alzheimer’s disease-associated pathology,and Wnt-5a was injected as a potential therapeutic treatment.Immunofluorescence staining showed that compared with normal rats,Aβ25-35 significantly decreased postsynaptic density-95 protein expression in the rat hippocampal CA1 region,but Wnt-5a pretreatment blocked this decrease.This study shows that Wnt-5a can reduce Aβ-induced cognitive impairment,and that it has the potential to be a new therapeutic strategy for the treatment of Alzheimer’s disease.     

δ-Opioid receptor as a potential therapeutic target for ischemic stroke

Ischemic stroke is a global epidemic condition due to an inadequate supply of blood and oxygen to a specific area of brain either by arterial blockage or by narrowing of blood vessels.Despite having advancement in the use of thrombolytic and clot removal medicine,significant numbers of stroke patients are still left out without option for treatment.In this review,we summarize recent research work on the activation ofδ-opioid receptor as a strategy for treating ischemic stroke-caused neuronal injury.Moreover,as activation ofδ-opioid receptor by a non-peptidicδ-opioid receptor agonist also modulates the expression,maturation and processing of amyloid precursor protein andβ-secretase activity,the potential role of these effects on ischemic stroke caused dementia or Alzheimer’s disease are also discussed.     

Amyloid beta-peptide worsens cognitive impairment following cerebral ischemia-reperfusion injury

Amyloid β-peptide,a major component of senile plaques in Alzheimer’s disease,has been implicated in neuronal cell death and cognitive impairment.Recently,studies have shown that the pathogenesis of cerebral ischemia is closely linked with Alzheimer’s disease.In this study,a rat model of global cerebral ischemia-reperfusion injury was established via occlusion of four arteries;meanwhile,fibrillar amyloidβ-peptide was injected into the rat lateral ventricle.The Morris water maze test and histological staining revealed that administration of amyloidβ-peptide could further aggravate impairments to learning and memory and neuronal cell death in the hippocampus of rats subjected to cerebral ischemia-reperfusion injury.Western blot showed that phosphorylation of tau protein and the activity of glycogen synthase kinase 3βwere significantly stronger in cerebral ischemia-reperfusion injury rats subjected to amyloid β-peptide administration than those undergoing cerebral ischemia-reperfusion or amyloidβ-peptide administration alone.Conversely,the activity of protein phosphatase 2A was remarkably reduced in rats with cerebral ischemia-reperfusion injury following amyloidβ-peptide administration.These findings suggest that amyloidβ-peptide can potentiate tau phosphorylation induced by cerebral ischemia-reperfusion and thereby aggravate cognitive impairment.     

Lamotrigine protects against cognitive deficits,synapse and nerve cell damage,and hallmark neuropathologies in a mouse model of Alzheimer's disease

Lamotrigine(LTG) is a widely used drug for the treatment of epilepsy. Emerging clinical evidence suggests that LTG may improve cognitive function in patients with Alzheimer’s disease. However, the underlying molecular mechanisms remain unclear. In this study, amyloid precursor protein/presenilin 1(APP/PS1) double transgenic mice were used as a model of Alzheimer’s disease. Five-month-old APP/PS1 mice were intragastrically administered 30 mg/kg LTG or vehicle once per day for 3 successive months....     

Toxic tau: structural origins of tau aggregation in Alzheimer's disease

Alzheimer’s disease is characterized by the extracellular accumulation of the amyloidβin the form of amyloid plaques and the intracellular deposition of the microtubule-associated protein tau in the form of neurofibrillary tangles.Most of the Alzheimer’s drugs targeting amyloidβhave been failed in clinical trials.Particularly,tau pathology connects greatly in the pathogenesis of Alzheimer’s disease.Tau protein enhances the stabilization of microtubules that leads to the appropriate function of the neuron.Changes in the quantity or the conformation of tau protein could affect its function as a microtubules stabilizer and some of the processes wherein it is involved.The molecular mechanisms leading to the accumulation of tau are principally signified by numerous posttranslational modifications that change its conformation and structural state.Therefore,aberrant phosphorylation,as well as truncation of tau protein,has come into focus as significant mechanisms that make tau protein in a pathological entity.Furthermore,the shape-shifting nature of tau advocates to comprehend the progression of Alzheimer’s disease precisely.In this review,we emphasize the recent studies about the toxic and shape-shifting nature of tau in the pathogenesis of Alzheimer’s disease.     

Characterization of hippocampal Cajal-Retzius cells during development in a mouse model of Alzheimer＇s disease （Tg2576）

Cajal-Retzius cells are reelin-secreting neurons in the marginal zone of the neocortex and hippocampus. The aim of this study was to investigate Cajal-Retzius cells in Alzheimer＇s disease pathology. Results revealed that the number of Cajal-Retzius cells markedly reduced with age in both wild type and in mice over-expressing the Swedish double mutant form of amyloid precursor protein 695 （transgenic （Tg） 2576 mice）. Numerous reelin-positive neurons were positive for activated caspase 3 in Tg2576 mice, suggesting that Cajal-Retzius neuronal loss occurred via apoptosis in this Alzheimer＇s disease model. Compared with wild type, the number of Cajal-Retzius cells was significantly lower in Tg2576 mice. Western blot analysis confirmed that reelin levels were markedly lower in Tg2576 mice than in wild-type mice. The decline in Cajal-Retzius cells in Tg2576 mice was found to occur concomitantly with the onset of Alzheimer＇s disease amyloid pathology and related behavioral deficits. Overall, these data indicated that Cajal-Retzius cell loss occurred with the onset and development of Alzheimer＇s disease.     

1000/铅暴露早期诱导成年大鼠视网膜神经元BACE-1表达上调

Previous studies have reported that non-human primates and rodents exposed to lead during brain development may become dependent on the deposition of pre-determined β-amyloid protein (Aβ),and exhibit upregulation of β-site amyloid precursor protein expression in old age.However,further evidence is required to elucidate the precise relationship and molecular mechanisms underlying the effects of early lead exposure on excessive Aβ production in adult mammals.The present study investigated the effects of lead exposure on expression of β-amyloid precursor protein cleavage enzyme-1 (BACE-1) in the rat retina and the production of Aβ in early development,using the retina as a window for studying Alzheimer’s disease.Adult rats were intraocularly injected with different doses of lead acetate (10μmol/L,100μmol/L,1 mmol/L,10 mmol/L and 100 mmol/L).The results revealed that retinal lead concentration,BACE-1 and its cleavage products β-C-terminal fragment and retina Aβ1-40 were all significantly increased in almost all of the lead exposure groups 48 hours later in a dose-dependent manner.The only exception was the 10μmol/L group.The distribution of BACE-1 in the retina did not exhibit obvious changes,and no distinctive increase in the activation of retinal microglia was apparent.Similarly,retinal synaptophysin expression did not exhibit any clear changes.These data suggest that lead exposure can result in the upregulation of retinal neuron BACE-1 expression in the early period of development and further increase the overproduction of Aβ1-40 in the retina.Our results provided novel insight into the molecular mechanisms underlying environmentally-induced Alzheimer’s disease.     

Targeting 13-secretase with RNAi in neural stem cells for Alzheimer＇s disease therapy

There are several major pathological changes in Alzheimer＇s disease, including apoptosis of cho- linergic neurons, overactivity or overexpression of 13-site amyloid precursor protein cleaving enzyme 1 （BACE1） and inflammation. In this study, we synthesized a 19-nt oligonucleotide targeting BACE1, the key enzyme in amyloid beta protein （AI3） production, and introduced it into the pSilenCircle vector to construct a short hairpin （shRNA） expression plasmid against the BACE1 gene. We transfected this vector into C17.2 neural stem cells and primary neural stem cells, resulting in downregulation of the BACE1 gene, which in turn induced a considerable reduction in reducing AI3 protein production. We anticipate that this technique combining cell transplantation and gene ther- apy will open up novel therapeutic avenues for Alzheimer＇s disease, particularly because it can be used to simultaneously target several pathogenetic changes in the disease.     

Beta secretase activity in peripheral nerve regeneration

While the peripheral nervous system has the capacity to regenerate following a nerve injury, it is often at a slow rate and results in unsatisfactory recovery, leaving patients with reduced function. Many regener-ation associated genes have been identified over the years, which may shed some insight into how we can manipulate this intrinsic regenerative ability to enhance repair following peripheral nerve injuries. Our lab has identified the membrane bound protease beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1), or beta secretase, as a potential negative regulator of peripheral nerve regeneration. When beta secretase activity levels are abolished via a null mutation in mice, peripheral regeneration is enhanced fol-lowing a sciatic nerve crush injury. Conversely, when activity levels are greatly increased by overexpressing beta secretase in mice, nerve regeneration and functional recovery are impaired after a sciatic nerve crush injury. In addition to our work, many substrates of beta secretase have been found to be involved in reg-ulating neurite outgrowth and some have even been identified as regeneration associated genes. In this review, we set out to discuss BACE1 and its substrates with respect to axonal regeneration and speculate on the possibility of utilizing BACE1 inhibitors to enhance regeneration following acute nerve injury and potential uses in peripheral neuropathies.     

Inhibition of BACE1, the β-secretase implicated in Alzheimer’s disease,by a chondroitin sulfate extract from Sardina pilchardus

The pharmaceutical and anticoagulant agent heparin,a member of the glycosaminoglycan family of carbohydrates,has previously been identified as a potent inhibitor of a key Alzheimer’s disease drug target,the primary neuronalβ-secretase,β-site amyloid precursor protein cleaving enzyme 1(BACE1).The anticoagulant activity of heparin has,however,precluded the repurposing of this widely used pharmaceutical as an Alzheimer’s disease therapeutic.Here,a glycosaminoglycan extract,composed predominantly of 4-sulfated chondroitin sulfate,has been isolated from Sardina pilchardus,which possess the ability to inhibit BACE1(IC50[half maximal inhibitory concentration]=4.8μg/mL),while displaying highly attenuated anticoagulant activities(activated partial thromboplastin time EC50[median effective concentration]=403.8μg/mL,prothrombin time EC50=1.3 mg/mL).The marine-derived,chondroitin sulfate extract destabilizes BACE1,determined via differential scanning fluorimetry(ΔTm–5°C),to a similar extent as heparin,suggesting that BACE1 inhibition by glycosaminoglycans may occur through a common mode of action,which may assist in the screening of glycan-based BACE1 inhibitors for Alzheimer’s disease.     

20S proteasome and glyoxalase 1 activities decrease in erythrocytes derived from Alzheimer’s disease patients

As a result of accumulating methylglyoxal and advanced glycation end products in the brains of patients with Alzheimer’s disease,it is considered a protein precipitation disease.The ubiquitin proteasome system is one of the most important mechanisms for cells to degrade proteins,and thus is very important for maintaining normal physiological function of the nervous system.This study recruited 48 individuals with Alzheimer’s disease(20 males and 28 females aged 75±6 years)and 50 healthy volunteers(21 males and 29 females aged 72±7 years)from the Affiliated Hospital of Youjiang Medical University for Nationalities(Baise,China)between 2014 and 2017.Plasma levels of malondialdehyde and H2O2 were measured by colorimetry,while glyoxalase 1 activity was detected by spectrophotometry.In addition,20S proteasome activity in erythrocytes was measured with a fluorescent substrate method.Ubiquitin and glyoxalase 1 protein expression in erythrocyte membranes was detected by western blot assay.The results demonstrated that compared with the control group,patients with Alzheimer’s disease exhibited increased plasma malondialdehyde and H2O2 levels,and decreased glyoxalase 1 activity;however,expression level of glyoxalase 1 protein remained unchanged.Moreover,activity of the 20S proteasome was decreased and expression of ubiquitin protein was increased in erythrocytes.These findings indicate that proteasomal and glyoxalase activities may be involved in the occurrence of Alzheimer’s disease,and erythrocytes may be a suitable tissue for Alzheimer’s disease studies.This study was approved by the Ethics Committee of Youjiang Medical University for Nationalities(approval No.YJ12017013)on May 3,2017.     

Cellular and molecular mechanisms underlying the action of ginsenoside Rg1 against Alzheimer's disease

Ginsenoside Rg1 inhibits oxidation, aging and cell apoptosis, and improves cognitive function. In this study, we pretreated rat brain tissue sections with ginsenoside Rg1, and established brain slice models of Alzheimer’s disease induced by okadaic acid. The results revealed that ginsenoside Rg1 pretreatment suppressed the increase in phosphorylated Tau protein expression induced by incubation with okadaic acid, and reduced brain-derived neurotrophic factor expression. These results suggest that ginsenoside Rg1 upregulates brain-derived neurotrophic factor expression and inhibits Tau protein phosphorylation in brain slices from a rat model of Alzheimer’s disease.     

Transient axonal glycoprotein-1 induces apoptosis- related gene expression without triggering apoptosis in U251 glioma cells

Previous studies show that transient axonal glycoprotein-1, a ligand of amyloid precursor pro- tein, increases the secretion of amyloid precursor protein intracellular domain and is involved in apoptosis in Alzheimer＇s disease. In this study, we examined the effects of transient axonal glyco- protein-1 on U251 glioma cells. 3-（4,5-Dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide assay showed that transient axonal glycoprotein-1 did not inhibit the proliferation of U251 cells, but promoted cell viability. The terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed that transient axonal glycoprotein-1 did not induce U251 cell apoptosis. Real-time PCR revealed that transient axonal glycoprotein-1 substantially upregulated levels of amyloid precursor protein intracellular C-terminal domain, and p53 and epidermal growth factor recep- tor mRNA expression. Thus, transient axonal glycoprotein-1 increased apoptosis-related gene expression in U251 cells without inducing apoptosis. Instead, transient axonal glycoprotein-1 promoted the proliferation of these glioma cells.