Research progresses of resting-state functional MRI in mild cognitive impairment and Alzheimer's disease

Alzheimer's disease(AD)is a prevalent neurodegenerative disease characterized by cognitive decline in the early stage.Mild cognitive impairment(MCI)is considered as an intermediate stage between normal aging and AD.In recent years,studies related to resting-state functional MRI(rs-fMRI)indicated that the occurrence and development process of MCI and AD might be closely linked to spontaneous brain activity and alterations in functional connectivity among brain regions,and rs-fMRI could provide important reference for specific diagnosis and early treatment of MCI and AD.The research progresses of rs-fMRI for MCI and AD were reviewed in this article.

Modulation of synaptic damage by Bushen Tiansui Decoction via the PI3K signaling pathway in an Alzheimer’s disease model

Objective To explore the therapeutic effect and mechanism of Bushen Tiansui Decoction(补肾填髓方,BSTSD)and its active component icariin on Alzheimer’s disease(AD).Methods(i)Animal experiments.This study conducted experiments using specific pathogen-free(SPF)grade male C57BL/6J wild-type(WT)mice and APP/PS1 double transgenic mice.The animals were divided into three groups:WT group(WT mice,n=5,receiving distilled wa-ter daily),APP/PS1 group(APP/PS1 double transgenic mice,n=5,receiving distilled water daily),and BSTSD group[APP/PS1 double transgenic mice,n=5,treated with BSTSD suspen-sion at a dosage of 27 g/(kg·d)for 90 d].Cognitive function was assessed using the Morris wa-ter maze(MWM).Post-experiment,hippocampal tissues were collected for analysis of pyra-midal cell and synaptic morphology through hematoxylin-eosin(HE)staining and transmis-sion electron microscopy(TEM).(ii)Cell experiments.The HT-22 cells were divided into con-trol group(untreated),Aβ_(25-35) group(treated with 20μmol/L Aβ_(25-35) for 24 h),icariin group(pre-treated with 20μmol/L icariin for 60 min,followed by 20μmol/L Aβ_(25-35) for an additional 24 h),and icariin+LY294002 group[treated with 20μmol/L icariin and 20μmol/L LY294002(an inhibitor of the phosphoinostitide 3-kinases(PI3K)signaling pathway)for 60 min,then exposed to 20μmol/L Aβ_(25-35) for 24 h],and cell viability was measured.Western blot was used to detect the expression levels of synapse-associated proteins[synaptophysin(SYP)and post-synaptic density-95(PSD-95)]and PI3K signaling pathway associated proteins[phosphorylat-ed(p)-PI3K/PI3K,p-protein kinase B(Akt)/Akt,and p-mechanistic target of rapamycin(mTOR)/mTOR].Results(i)Animal experiments.Compared with APP/PS1 group,BSTSD group showed that escape latency was significantly shortened(P<0.01)and the frequency of crossing the origi-nal platform was significantly increased(P<0.01).Morphological observation showed that pyramidal cells in the hippocampal CA1 region were arranged more regularly,nuclear stain-ing was uniform,and vacuole-like changes were reduced after BSTSD treatment.TEM showed that the length of synaptic active zone in BSTSD treatment group was increased com-pared with APP/PS1 group(P<0.01),and the width of synaptic gap was decreased(P<0.01).(ii)Cell experiments.Icariin had no obvious toxicity to HT-22 cells when the concentration was not more than 20μmol/L(P>0.05),and alleviated the cell viability decline induced by Aβ_(25-35)(P<0.01).Western blot results showed that compared with Aβ_(25-35) group,the ratios of p-PI3K/PI3K,p-Akt/Akt and p-mTOR/mTOR in icariin group were significantly increased(P<0.01),while the protein expression levels of SYP and PSD-95 were increased(P<0.01).These effects were blocked by LY294002(P<0.01).Conclusion BSTSD and icariin enhance cognitive function and synaptic integrity in AD mod-els and provide potential therapeutic strategies through activation of the PI3K/Akt/mTOR pathway.

Alzheimer’s disease:epidemiology,genetics,and beyond

Alzheimer＇s disease （AD） is an increasing epidemic threatening public health. Both men and women are susceptible to the disease although women are at a slightly higher risk. The prevalence of AD rises exponentially in elderly people from 1% at age of 65 to approximately 40%-50% by the age of 95. While the cause of the disease has not been fully understood, genetics plays a role in the onset of the disease. Mutations in three genes （APP, PSENI, and PSEN2） have been found to cause AD and APOE4 allele increases the risk of the disease. As human genomic research progresses, more genes have been identified and linked with AD. Genetic screening tests for persons at high risk of AD are currently available and may help them as well as their families better prepare for a later life with AD.

Genetic predisposition to inflammation:a new risk factor of Alzheimer's disease

Inflammation has been shown to play an important role in the progression of Alzheimer＇s disease （AD）. Recent epidemical study indicates that the incidence of AD in some populations is substantially influenced by the gene polymorphisms of the inflammation mediators. Meanwhile, an ensured risk factor, the ApoE ε4 allele is also reported to directly promote inflammation. Accordingly, it appears that an individual genetic background has partly determined his predisposition for AD by the extent of the inflammation response to the chronic stimulus by β-amyloid peptide （Aβ） deposits and other antigen stressor in the elderly. Hence we present a hypothesis that the inflammation genotypes may contribute to AD susceptibility. This may provide a new orientation both for future identification of individuals at risk and for personalized medication.

The Value of CSF Level of β- amyloid Protein in the Diagnosis of Alzheimer's Disease

Objective:To evaluate the diagnostic potential of cerebrospmal fluid (CSF) levels of β-amyloid protein (Aβ) as biochemical marker for senile dementia in clinical practice. Methods : Sensitive enzyme-linked immunosorbent assay (ELISA) was performed in our lalxrratory to delect the CSF levels of Aβt-40, Aβ1-42 in 54 patients with Alzlteimer's disease (AD), and 30 normal controls (NC). Results: The cut off value of Aβ ratio and Aβ1-42 concentration in NC group provided 54. 51%, 90. 00% sensitivity and 81. 25%, 84. 38% specificity respectively in diagnosis of AD. Conclusion : AD group had a significant decreased level of Aβ1-42 and an increased level of Aβ ratio, compared with NC group.

安特卫普港经营管理考察

一、安特卫普港在比利时的地位安特卫普港位于斯堪尔德——默茨——莱茵三角州。全长1500公里的比利时内河航线,由它同欧洲水陆交通网相连,港口区域紧靠斯堪尔德河沿岸,港区总面积17800公顷,码头岸线总长90.9公里,共有22个港池。主要进出口货物有钢铁、石油化学产品、粮食、奶油、纤维品及矿物等,年吞吐量达9000万吨。比利时的对外贸易在国民经济中占有很大的比重,出口货物占全国总产值的55%,比利时水运的80%,铁路的65%和公里的33%运量都是为外贸服务的。

深入《山海经》研究,探索美洲文明起源

美洲原住民强烈反对“哥伦布发现新大陆”的神话。哥伦布带给美洲人的是侵略、奴役与大屠杀。而200多年来,众多中外学者热心研究表明,中国人在早于哥伦布一千年乃至三、四千年前就发现了这块大陆。美国默茨博士《几近褪色的记录》通过对中国古籍《山海经》的研究,认为“中国人至少在公元前2200年就已到达美洲”。而以中国太平洋学会研究员王大有、宋宝忠以及笔者多年的研究,更从体质人类学、图腾学、语言学、古文字学、古代地图学等多方面雄辩地考证出,多批中国人确实先于哥伦布到达美洲。

Is Glucagon-like peptide-1, an agent treating diabetes, a new hope for Alzheimer's disease?

Glucagon-like peptide- 1 （GLP- 1） has been endorsed as a promising and attractive agent in the treatment of type 2 diabetes mellitus （T2DM）. Both Alzheimer＇s disease （AD） and T2DM share some common pathophysiologic hallmarks, such as amyloid β （Aβ）, phosphoralation of tau protein, and glycogen synthase kinase-3. GLP-1 possesses neurotropic properties and can reduce amyloid protein levels in the brain. Based on extensive studies during the past decades, the understanding on AD leads us to believe that the primary targets in AD are the Aβ and tau protein. Combine these findings, GLP- 1 is probably a promising agent in the therapy of AD. This review was focused on the biochemistry and physiology of GLP- 1, communities between T2DM and AD, new progresses of GLP - 1 in treating T2MD and improving some pathologic hanmarks of AD.

New lead discovery for novel M_1 agonists:pharmacophore model based on DISCO computation and virtual screening

To discover new lead compounds for M1 agonists. Ten typical M1 agonists were superimposed to build a M1 agonists 3D-pharmacophore model using distance-comparisons （DISCO） method without the previous knowledge of the three-dimensional structure of M1 receptor. Virtual screening strategy was used to analyze the Available Chemicals Directory-Screening Compounds （ACD-SC） to identify possible new hits. Twenty-two compounds which fit the pharmacophore model well and are not similar with known M1 agonists were purchased in order to evaluate their M1 receptor agonist activity. One of them shows M1 receptor agonist activity with EC50 of 4.90 μmol/L and maximum response. Multiple of 10.0 which shows it worthy of further study as a new lead compound for M1 agonists.

RELATIONSHIP OF HOMOCYSTEINE AND GENE POLYMORPHISMS OF ITS RELATED METABOLIC ENZYMES WITH ALZHEIMER'S DISEASE

Objective To investigate the relationship of plasma homocysteine (Hcy) levels and the gene polymorphisms of N5, N10-methylenetetrahydrofolate reductase (MTHFR), cystathionine β-synthase (CBS) with Alzheimer’s disease (AD). Methods Plasma Hcy levels were measured by means of high voltage capillary electrophoresis with ultra-violet detection, the polymorphisms of C677T in exon 4 of MTHFR gene and 844ins68 in exon 8 of CBS gene were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 105 AD patients and 102 non-AD controls. All controls were excluded from cardiocerebrovascular disorders and other diseases. Results The plasma Hcy level in AD patients (16.04 ± 3.84 μmol/L) was significantly higher than that in the controls(11.94 ± 3.87 μmol/L, P < 0.001). There were no significant differences of the genotype and allele frequencies of MTHFR C677T mutation and CBS 844ins68 mutation between the patients and controls. However, the T allele of MTHFR gene was found to relate with the plasma Hcy level increase in all subjects. Conclusion The elevated plasma Hcy level in AD patients is probably involved in the pathogenesis of AD, which may be due to the environmental factor rather than genetic factors of the mutations of MTHFR and CBS.

Therapeutic targets and delivery challenges for Alzheimer's disease

Dementia, including Alzheimer’s disease, the 21^st Century epidemic, is one of the most signifcant social and health crises which has currently afficted nearly 44 million patients worldwide and about new 7.7 million cases are reported every year. This portrays the unmet need towards better understanding of Alzheimer’s disease pathomechanisms and related research towards more effective treatment strategies. The review thus comprehensively addresses Alzheimer’s disease pathophysiology with an insight of underlying multicascade pathway and elaborates possible therapeutic targets- particularly anti-amyloid approaches, anti-tau approaches, acetylcholinesterase inhibitors, glutamatergic system modifiers, immunotherapy, anti-nflammatory targets, antioxidants, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors and insulin. In spite of extensive research leading to identification of newer targets and potent drugs, complete cure of Alzheimer’s disease appears to be an unreached holy grail. This can be attributed to their ineffective delivery across blood brain barrier and ultimately to the brain. With this understanding, researchers are now focusing on development of drug delivery systems to be delivered via suitable route that can circumvent blood brain barrier effectively with enhanced patient compliance. In this context, we have summarized current drug delivery strategies by oral, transdermal, intravenous, intranasal and other miscellaneous routes and have accentuated the future standpoint towards promising therapy ultimately eading to Alzheimer’s disease cure.

A GPCR/secretase complex regulates β- and γ-secretase specificity for Aβ production and contributes to AD pathogenesis

Dysregulation of β-site APP-cleaving enzyme （BACE） and/or γ-secretase leads to anomalous production of amyloid-β peptide （Aβ） and contributes to the etiology of Alzheimer＇s disease （AD）. Since these secretases mediate proteolytic processing of numerous proteins, little success has been achieved to treat AD by secretase inhibitors because of inevitable undesired side effects. Thus, it is of importance to unravel the regulatory mechanisms of these secretases. Here, we show that δ-opioid receptor （DOR） promotes the processing of Aβ precursor protein （APP） by BACE1 and γ-secretase, but not that of Notch, N-cadherin or APLP. Further investigation reveals that DOR forms a complex with BACE1 and γ-seeretase, and activation of DOR mediates the co-endocytic sorting of the secretases/ receptor complex for APP endoproteolysis. Dysfunction of the receptor retards the endocytosis of BACE1 and γ-secretase and thus the production of Aβ Consistently, knockdown or antagonization of DOR reduces secretase activities and ameliorates Aβ pathology and Aβ-dependent behavioral deficits, but does not affect the processing of Notch, N-cadherin or APLP in AD model mice. Our study not only uncovers a molecular mechanism for the formation of a DOR/secretase complex that regulates the specificity of secretase for Aβ production but also suggests that intervention of either formation or trafficking of the GPCR/secretase complex could lead to a new strategy against AD, potentially with fewer side effects.

Biomarkers of neurodegenerative disorders: How good are they?

Biomarkers are very important indicators of normal and abnormal biological processes. Specific changes in pathologies, biochemistries and genetics can give us comprehensive information regarding the nature of any particular disease. A good biomarker should be precise and reliable, distinguishable between normal and interested disease, and differential between different diseases. It is believed that biomarkers have great potential in predicting chances for diseases, aiding in early diagnosis, and setting standards for the development of new remedies to treat diseases. New technologies have enabled scientists to identify biomarkers of several different neurodegenerative diseases. The followings, for instance, are only a few of the many new biomarkers that have been recently identified: the phosphorylated tau protein and aggregated β-amyloid peptide for Alzheimer’s disease (AD), α-synuclein contained Lewy bodies and altered dopamine transporter (DAT) imaging for Parkinson’s disease (PD), SOD mutations for familial amyotrophic lateral sclerosis (ALS), and CAG repeats resulted from Huntington’s gene mutations in Huntington’s disease (HD). This article will focus on the most-recent findings of biomarkers belonging to the four mentioned neurodegenerative diseases.

ASSOCIATION BETWEEN LOW- DENSITY LIPOPROTEIN RECEPTOR- RELATED PROTEIN GENE, BUTYRYLCHOLINESTERASE GENE AND ALZHEIMER'S DISEASE IN CHINESE

Objective. To research the relations between low- density lipoprotein receptor- related protein gene (LRP) polymorphism, butyrylcholinesterase gene (BchE) polymorphism and Alzheimer’s disease (AD) in Chinese. Methods. The gene polymorphisms of LRP and BchE were genotyped in 38 AD cases and 40 controls with polymerase chain reaction- restriction fragment length polymorphism (PCR- RFLP) methods. AD groups were classified according to the LRP C/C genotype and compared with matched controls. Results. AD group had higher frequencies of C/C homozygote (81.6％ vs 60.0％ , P< 0.05) and of C allele (89.5％ vs 76.3％ , P< 0.05),with no significant difference between any of these LRP genotypes classified AD groups and their respective control groups. Conclusions. A positive correlation was found between LRP gene polymorphism and AD, but not between BchE gene polymorphism and AD in Chinese AD cases.

The pathogenesis of Alzheimer and pharmaceutical research on prevention

Senile Dementia is the illness with a symptom of ongoing cognitive obstacle and loss of memory function. With our population aging, dementia and depression in old age is increasing rapidly. It is estimated that by 2020, depressive disorder will become the second largest human disease leading to crippling. By 2040, globally the number of people with dementia will reach 81.1 million while the number of dementia patients in China will be the sum of that in all developed countries. Its incidence increases exponentially with age and the incidence of the elderly over 85 reach up to 8% -10%. Among all dementia patients, people with Alzheimer＇ s disease （Alzheimer＇ s disease, AD） accounted for 50 % -70%, the rest is vascular dementia （vascular dementia, VD） and mixed dementia. In the United States, Alzheimer＇ s disease has become the fourth leading cause of death followed after cardiovascular disease, cancer and stroke. Through comprehensive control strategy, we can improve the mental health level of old people, so as to protect the physical and mental health, improving the life quality of old people.

Investigation on apoptosis of neuronal cells induced by Amyloid beta-Protein

Objective: To construct a PC12 cell strain with neuronal differentiation, and observe the apoptosis and pro- liferation activity effects induced these cells by Amyloid beta-Protein (Aβ-43). Methods: 1) PC12 cells in logarithmic growth phase were subcultured for 24 h. After the culture fluid was changed, the cells were treated with Rat-β-NGF and cultured for 9 days. 2) Neuronal differentiation of PC12 cells in logarithmic growth phase were divided into four groups: control group (0), experimental group (1), experimental group (2) and experimental group (3). The concentrations of Aβ in the four groups were 0 μmol/L, 1.25 μmol/L, 2.5 μmol/L and 5 μmol/L, respectively. The cells were harvested at 24, 48 and 72 h later and stained with AnnexinV-FITC/PI after centrifugation and washing. Then flow cytometry was conducted to examine the apoptosis percentage. 3) NGF-induced PC12 cells were selected and Aβ with different concentrations was added. The final concentrations of Aβ were 0 μmol/L, 1.25 μmol/L, 2.5 μmol/L and 5 μmol/L, respectively. After the cells were incubated in an atmosphere of 5% CO2 at 37 °C in an incubator for 72 h, the OD values were examined. Results: 1) Neuronal differentiated PC12 cell lines were successfully established. 2) Flow cytometric examination indicated that Aβ (1.25, 2.5, and 5.0 μmol/L) could effectively induce apoptosis of neuronal-differented cells at the 24 h, 48 h and 72 h time points. 3) Aβ (0?5.00 μmol/L) had no obvious effect on proliferation or restraining of the neuronal differentiation of the PC12 cells after a 72 h interacting process. Conclusion: This investigation revealed successful neuronal differentiation of the PC12 cell strain. The induction of apoptosis of the neurocytes by various concentrations of Aβ was observed and the in- fluence of Aβ on induced proliferation of PC12 cells by Rat-β-NGF was revealed. This study may provide basis for future research on the molecular cure of AD and interdiction of AD evolution.

Effect of amyloid peptides on serum withdrawal-induced cell differentiation and cell viability

Abnormal deposition of amyloid-p(Ap) peptides and formation of neuritic plaques are recognized as pathological processes in Alzheimer's disease (AD) brain. By using amyloid precursor protein (APP) transfected cells, this study aims to investigate the effect of overproduction of Aβ on cell differentiation and cell viability. It was shown that after serum withdrawal, untransfected cell (N2a/Wt) and vector transfected cells (N2a/vector) extended long and branched cell processes, whereas no neurites was induced in wild type APP (N2a/APP695) and Swedish mutant APP (N2a/ APPswe) transfected N2a cells. After differentiation by serum withdrawal, the localization of APP/AP and neurofilament was extended to neurites, whereas those of APP-transfected cells were stillrestricted within the cell body. Levels of both APP and Aβ were significantly higher in N2a/APP695 and N2a/APPswe than in N2a/Wt, as determined by Western blot and Sandwich ELISA, respectively. To further investigate the effect of A0 on the inhibition of cell differentiation, we added exogenously the similar level or about 10-times of the AP level produced by N2a/APP695 and N2a/APPswe to the culture medium and co-cultured with N2a/Wt for 12 h, and we found that the inhibition of serum withdrawal-induced differentiation observed in N2a/APP695 and N2a/APPswe could not be reproduced by exogenous administration of AP into N2a/Wt. We also observed that neither endogenous production nor exogenous addition of Aβ1-40 or Aβ1-42, even to hundreds fold of the physiological concentration, affected obviously the cell viability. These results suggest that the overproduction of AP could not arrest cell differentiation induced by serum deprivation and that, at least to a certain degree and in a limited time period, is not toxic to cell viability.

Neurotoxicity and Biomarkers of Lead Exposure: a Review

Appropriate selection and measurement of lead biomarkers of exposure are critically important for health care management purposes,public health decision making,and primary prevention synthesis.Lead is one of the neurotoxicants that seems to be involved in the etiology of psychologies.Biomarkers are generally classified into three groups:biomarkers of exposure,effect,and susceptibility.The main body compartments that store lead are the blood,soft tissues,and bone;the half-life of lead in these tissues is measured in weeks for blood,months for soft tissues,and years for bone.Within the brain,lead-induced damage in the prefrontal cerebral cortex,hippocampus,and cerebellum can lead to a variety of neurological disorders,such as brain damage,mental retardation,behavioral problems,nerve damage,and possibly Alzheimer’s disease,Parkinson’s disease,and schizophrenia.This paper presents an overview of biomarkers of lead exposure and discusses the neurotoxic effects of lead with regard to children and adults.

D-Tyr-tRNA^(Tyr) Deacylase,a New Role in Alzheimer's-associated Disease in SAMP8 Mice

Objective To assess the expression level of D-Tyr-tRNATyr deacylase(DTD) in SAMP8 mice and speculate the function of DTD in disorders associated with Alzheimer's disease(AD).Methods Altogether 12 SAMP8 mice and 12 SAMR1 mice were used in this study.Semi-quantita-tive reverse transcription-polymerase chain reaction(RT-PCR) and Western blot were performed to detect the mRNA and protein levels of DTD in the mice.Purified DTD protein was injected into lateral ventricle to investigate the function of DTD in SAMP mice.The behavior of the mice was tested by using a Step-through Test System.Results Both mRNA and protein levels of DTD were found to be significantly lower in SAMP8 mice compared with those in SAMR1 mice(P<0.05).In vivo injection of DTD protein did not lead to an obvious change in behavior of SAM mice.Conclusions DTD might function in the process of AD-associated pathology and could possibly participate in physiology process in a long-term manner to orchestrate with other regulators in order to maintain the balance of organism.

APOLIPOPROTEIN E POLYMORPHISM AND ALZHERMER'S DISEASE

We determined and analysed the ApoE polymorphism of 30 sporadic Alzheimer’s disease (AD) pa- tients, 27 patients with multi-infarct dementia (MID) and 46 aged healthy subjects as control. The results showed that the frequency of ApoE E4/3 genetype in AD group was significantly higher than that in con- trol (P<0. 05). Among these three groups, ApoE 4 allele frequency in AD group was significantly higher than that in control (P<0. 01 ) and MID group (P<0. 05). Among the three ApoE alleles, the risk ratio of ApoE E4 allele in AD group was 4. 114(p<0. 01 ). There was statistically significant (P<0. 05) as the increasing of ApoE 4 gene dose in AD. It suggests that ApoE is related to AD of Chineses and it might be a genetics index of early diagnosis for AD.