Impact of apolipoprotein E isoforms on sporadic Alzheimer's disease:beyond the role of amyloid beta

The impact of apolipoprotein E(ApoE)isoforms on sporadic Alzheimer's disease has long been studied;however,the influences of apolipoprotein E gene(APOE)on healthy and pathological human brains are not fully understood.ApoE exists as three common isoforms(ApoE2,ApoE3,and ApoE4),which differ in two amino acid residues.Traditionally,ApoE binds cholesterol and phospholipids and ApoE isoforms display diffe rent affinities for their receptors,lipids transport and distribution in the brain and periphery.The role of ApoE in the human depends on ApoE isoforms,brain regions,aging,and neural injury.APOE E4 is the strongest genetic risk factor for sporadic Alzheimer's disease,considering its role in influencing amyloid-beta metabolism.The exact mechanisms by which APOE gene variants may increase or decrease Alzheimer's disease risk are not fully understood,but APOE was also known to affect directly and indirectly tau-mediated neurodegeneration,lipids metabolism,neurovascular unit,and microglial function.Consistent with the biological function of ApoE,ApoE4 isoform significantly alte red signaling pathways associated with cholesterol homeostasis,transport,and myelination.Also,the rare protective APOE variants confirm that ApoE plays an important role in Alzheimer's disease pathogenesis.The objectives of the present mini-review were to describe classical and new roles of various ApoE isoforms in Alzheimer's disease pathophysiology beyond the deposition of amyloid-beta and to establish a functional link between APOE,brain function,and memory,from a molecular to a clinical level.APOE genotype also exerted a heterogeneous effect on clinical Alzheimer's disease phenotype and its outcomes.Not only in learning and memory but also in neuro psychiatric symptoms that occur in a premorbid condition.Cla rifying the relationships between Alzheimer's disease-related pathology with neuropsychiatric symptoms,particularly suicidal ideation in Alzheimer's disease patients,may be useful for elucidating also the underlying pathophysiological process and its prognosis.Also,the effects of anti-amyloid-beta drugs,recently approved for the treatment of Alzheimer's disease,could be influenced by the APOE genotype.

27-Hydroxycholesterol/liver X receptor/apolipoprotein E mediates zearalenone-induced intestinal immunosuppression:A key target potentially linking zearalenone and cancer

Zearalenone(ZEN)is a mycotoxin that extensively contaminates food and feed,posing a significant threat to public health.However,the mechanisms behind ZEN-induced intestinal immunotoxicity remain unclear.In this study,Sprague-Dawley(SD)rats were exposed to ZEN at a dosage of 5 mg/kg/day b.w.for a duration of 14 days.The results demonstrated that ZEN exposure led to notable pathological alterations and immunosuppression within the intestine.Furthermore,ZEN exposure caused a significant reduction in the levels of apolipoprotein E(ApoE)and liver X receptor(LXR)(P<0.05).Conversely,it upregulated the levels of myeloid-derived suppressor cells(MDSCs)markers(P<0.05)and decreased the presence of 27-hydroxycholesterol(27-HC)in the intestine(P<0.05).It was observed that ApoE or LXR agonists were able to mitigate the immunosuppressive effects induced by ZEN.Additionally,a bioinformatics analysis highlighted that the downregulation of ApoE might elevate the susceptibility to colorectal,breast,and lung cancers.These findings underscore the crucial role of the 27-HC/LXR/ApoE axis disruption in ZEN-induced MDSCs proliferation and subsequent inhibition of T lymphocyte activation within the rat intestine.Notably,ApoE may emerge as a pivotal target linking ZEN exposure to cancer development.

Apolipoprotein E2 inhibits mitochondrial apoptosis in pancreatic cancer cells through ERK1/2/CREB/BCL-2 signaling

Background: Apolipoprotein E2(ApoE2) is a pleiotropic protein that influences several aspects of cancer metabolism and development. Evading apoptosis is a vital factor for facilitating cancer cell growth. However, the role and mechanism of ApoE2 in regulating cell apoptosis of pancreatic cancer remain unclear. Methods: In this study, we firstly detected the m RNA and protein expressions of ApoE2 in PANC-1 and Capan-2 cells by real-time polymerase chain reaction and Western blotting. We then performed TUNEL and flow cytometric analyses to explore the role of recombinant human ApoE2, p CMV6-ApoE2 and si ApoE2 in the apoptosis of PANC-1 and Capan-2 cells. Furthermore, we investigated the molecular mechanism through which ApoE2 affected apoptosis in PANC-1 cells using immunofluorescence, immunoprecipitation, Western blotting and co-immunoprecipitation analysis. Results: ApoE2 phosphorylated ERK1/2 and inhibited pancreatic cancer cell apoptosis. In addition, our data showed that ApoE2/ERK1/2 altered the expression and mitochondrial localization of BCL-2 via activating CREB. ApoE2/ERK1/2/CREB also increased the total BCL-2/BAX ratio, inhibited the opening of the mitochondrial permeability transition pore and the depolarization of mitochondrial transmembrane potential, blocked the leakage of cytochrome-c and the formation of the apoptosome, and consequently, suppressed mitochondrial apoptosis. Conclusions: ApoE2 regulates the mitochondrial localization and expression of BCL-2 through the activation of the ERK1/2/CREB signaling cascade to evade the mitochondrial apoptosis of pancreatic cancer cells. ApoE2 may be a distinct prognostic marker and a potential therapeutic target for pancreatic cancer.

Association of apolipoprotein E gene polymorphism with the occurrence and therapeutic effect of ischemic stroke

At present,ischemic stroke seriously affects people's life and health,and its occurrence,development and therapeutic effect are affected by many factors.With the deep research on ischemic cerebral apoplexy disease,people have a deeper understanding of its virulence genes.The apolipoprotein E genotype is the research focus recently,its genetic type is not only involved in the occurrence and development of ischemic cerebral apoplexy,but also causes different therapeatic effects.In this paper,we reviewed the relationship between apolipoprotein E gene polymorphism and lipid metabolism and atherosclerosis in ischemic stroke,as well as the differences in the therapeutic effects of thrombolysis,thrombectomy and lipid-lowering among different genotypes.

The Effects of Apolipoprotein E Polymorphism on Serum Lipids, Lipoproteins and Apolipoproteins Variation

Objective: To study the effects of Apolipoprotein E (ApoE) polymorphism onserum levels of lipids, lipoproteins and apolipoproteins. Methods: Fragments of ApoE gene forthex-on containing codon 112 and 158 polymorphic locus were amplified by PCR, and then digested untilCfo I endonuclease. Genotypes and alleles frequencies of 168 healthy persons in Jiangsu area werecalculated. The effects of ApoE genotypes and alleles on serum lipids, lipoproteins andapolipoproteins variation were analyzed. Results: The effects of ApoE alleles on total cholesterol(TC), law density lipoprotein-cholesterol (LDL-C), ApoB was: along a decreasing gradientε_4>ε_3>ε_2. The effect of ε_4 allele was to increase serum levels of TC, LDL-C and ApoB, andthe ε_2 allele had an effect opposite to that of ε_4 allele. Conclusion: ApoE polymorphism is anindependent genetic factor on individual serum levels of lipids and apolipoproteins.

Triglyceride levels and apolipoprotein E polymorphism in patients with acute pancreatitis

BACKGROUND:Hypertriglyceridemia is an unusual cause of acute pancreatitis and sometimes considered to be an epiphenomenon.This study aimed to investigate the clinical and analytical features and the APOE genotypes in patients with acute pancreatitis and severe hypertriglyceridemia.METHODS:We undertook a one-year,prospective study of patients with acute pancreatitis whose first laboratory analysis on admission to the emergency department included measurement of serum triglycerides.The APOE genotype was determined and the patients answered an established questionnaire within the first 24 hours concerning their alcohol consumption,the presence of co-morbidities and any medications being taken.The patients’ progression,etiological diagnosis,hospital stay and clinical and radiological severity were all recorded.RESULTS:Hypertriglyceridemia was responsible for 7 of 133 cases of pancreatitis (5%);the remaining cases were of biliary (53%),idiopathic (26%),alcoholic (11%) or other (5%) origin.Compared with these remaining cases,the patients with hypertriglyceridemia were significantly younger,had more relapses,and more often had diabetes mellitus.They usually consumed alcohol or consumed it excessively on the days before admission.Also,the ε4 allele of the APOE gene was more common in this group (P<0.05).CONCLUSION:One of 20 episodes of acute pancreatitis is caused by hypertriglyceridemia and it is linked to genetic (ε4 allele) and comorbid factors such as diabetes and,especially,alcohol consumption.

Apolipoprotein E polymorphisms increase the risk of post-stroke depression

Recent reports have shown that apolipoprotein E （APOE） polymorphisms are involved in neurodegenerative disease. However, it is unclear whether APOE affects post-stroke depression. Accordingly, we hypothesized that APOE polymorphisms modify the risk of post-stroke depression. Here, we performed a hospital-based case-control study （including 76 cerebral infarction cases with post-stroke depression, 88 cerebral infarction cases without post-stroke depression, and 109 controls without any evidence of post-stroke depression or cerebral infarction） to determine possible association between APOE rs429358 and rs7412 polymorphisms and risk of post-stroke depression. Our findings show no difference among the groups with regards genotype distribution of the rs7412 polymorphism. In contrast, APOE genotypes with rs429358-C alleles increased the risk of post-stroke depression. Further, the rs429358 polymorphism was associated with significantly decreased regional cerebral blood flow values in the left temporal lobe of post-stroke depression cases. Additionally, the rs429358 polymorphism was not only associated with depression severity, but with increasing serum levels of total cholesterol. These resuits suggest that the APOE rs429358 polymorphism is associated with increased risk of developing post-stroke depression, and that APOE rs429358-C allele genotypes may be detrimental to recovery of nerve function after stoke. Indeed, these findings provide clinical data for future post-stroke depression gene interventions.

APOLIPOPROTEIN E GENE POLYMORPHISMS AND RISK FOR CORONARY ARTERY DISEASE IN CHINESE XINJIANGUYGUR AND HAN POPULATION

Objective To examine the relationship between apolipoprotein E (Apo E) gene polymorphism and risk of coronary artery disease (CAD), analyzing association of polymorphism with classical risk factors. Methods A total of 124 patients (including 84 Han population and 40 Uygur population) with angiographically verified CAD or myocardial infarction were prospectively evaluated. Data referring to hypertension, diabetes, and tobacco consump-tion were recorded. The levels of total cholesterol (TC), high density lipoprotein (HDL) cholesterol, Apo A1 and B, and triglycerides (TG) were determined. DNA was obtained from 124 patients and 70 controls. In order to determine Apo E genotypes, DNA was PCR amplified and digested with HhaI. The genetic polymorphism of Apo E is due to three common alleles, epsilon(ε) 2, ε3, ε4, at a single autosomal gene locus. These alleles determine the six phenotypes E2/2, E3/3, E4/4, E4/2, E4/3, and E3/2. Results In Uygur population, the frequency of the ε2, ε3, and ε4 was 0.155, 0.648, and 0.197 respectively. In Han po-pulation, the frequency of the ε2, ε3, and ε4 was 0.081, 0.772, and 0.146 respectively. In the patient group, the frequency of the ε2, ε3, and ε4was 0.060, 0.758, and 0.182 respectively. In the control group, the frequency of the ε2, ε3, and ε4 was 0.193, 0.671, and 0.136 respectively. ε2 frequency of Uygur’ patients and controls was 0.050 and 0.290 respectively. Serum low density lipoprotein (LDL) cholesterol, TC, and TG values tended to decrease from the Apo E-4 phenotypes to Apo E-2 phenotypes. When deletion polymorphism of ε2 was compared with the common risk factors for CAD, its risk ratio (RR) is 4.38. Conclusions These studies confirm and find that Apo E phenotype distribution in Uygur population differs significantly from that in Han population in Xinjiang. CAD patients have significantly lower ε2 allele and slightly higher ε3 or ε4 allele frequency than controls, especially in Uygur population. It shows protective effects of ε2 on CAD.

Effect of apolipoprotein E gene Hha Ⅰ restricting fragment length polymorphism on serum lipids in cholecystolithiasis

AIM To investigate the role of apolipoprotein E (apoE) polymorphism in the lithogenesis of gallstone and the hereditary pathogenesis of the disease.METHODS Polymerase chain reaction (PCR)was used to study apoE phenotypes and allelefrequencies in patients with gallstones and control, and the fasting serum lipids of subjectswere also measured by enzymatic methods.RESULTS The levels of triglyceride (TG) andvery low density lipoprotein cholesterol (VLDLC) were much higher in Ez/, patients than that inE,/, control. E,/, patients were accompanied withremarkably low levels of high density lipoproteincholesterol (HDLC) and its subforms. But in E,/#patients there were only slight changes in levelsof VLDLC and low density lipoprotein cholesterol (LDL--C).CONCLUSION Different apoE phenotype patientswith gallstones have different cheracteristics ofdyslipidemia and the average level of serum lipids in patients with gallstones are higher thansubjects without gallstones in the same apoEgene phenotype. EZ allele is possibly one of thedangerous factors in the lithogenesis of cholecystolithiasis.

Apolipoprotein E gene polymorphism in cerebrovascular diseases of the Chinese Naxi populations from Yunnan province

Currently it is not well known whether apolipoprotein E （ApoE） is a genetic susceptibility factor for cerebrovascular diseases in the Chinese Naxi population. The present study detected and sequenced ApoE polymorphisms of 90 patients with cerebrovascular diseases （58 cases of cerebral infarction and 32 cases of intracerebral hemorrhage）, and 50 normal people of Naxi nationality from Yunnan province, China. The populations were used to analyze the relationship of ApoE polymorphisms with cerebral infarction and intracerebral hemorrhage. Results showed an association between ApoE gene polymorphism and the onset of cerebral infarction, and a possibility that the ε4 allele is a susceptibility locus for the risk of cerebral infarction. However, there was no evidence of a relationship between the ApoE gene polymorphism and cerebral hemorrhage.

Apolipoprotein E gene polymorphism and susceptibility to intracerebral hemorrhage:A meta-analysis

OBJECTIVE： To evaluate the relationship between apolipoprotein E （ApoE） gene polymorphism and susceptibility to intracerebral hemorrhage （ICH） in Chinese population by a meta-analysis. METHODS： Related literature regarding control analysis between ICH and control groups was collected. Independent case-control studies published between 1989 and 2007 that had complete data were included; and articles not closely related to the topic were excluded. The meta-analysis software, RevMan 4.2, was applied to analyze the odds ratio （OR） value in those studies included in the analysis to assess the relationship between susceptibility to ICH and ApoE polymorphism. RESULTS： Eight papers which were in accordance with the inclusion criteria were selected, and a total of 1 249 ICH cases and 1 329 controls were involved. Meta-analysis results showed that with the wildtype E3/3 as a reference, the OR values （95% confidence interval） of intracerebral hemorrhage for subjects carrying E2/2, E3/2, E4/2, E4/3, and E4/4 were 1.15 （0.60–2.21）, 1.00 （0.79–1.28）, 3.01 （1.73–5.23）, 1.78 （1.41–2.24） and 1.94 （1.03–3.65）, respectively. The combined OR values （95% confidence interval） of intracerebral hemorrhage for ε4 and ε2 carriers were 1.53 （1.16–2.01）, and 0.93 （0.69–1.25）. CONCLUSION： The results suggest that ApoE polymorphism is significantly associated with susceptibility to intracerebral hemorrhage and that ε4 carriers have a higher risk for intracerebral hemorrhage than others.

Apolipoprotein E mimetic peptide protects against diffuse brain injury

Apolipoprotein E plays a crucial role in inhibiting chronic neurodegenerative processes. Howev-er, its impact on neurological function following diffuse brain injury is still unclear. This study was designed to evaluate the therapeutic effects and mechanisms of action of apolipoprotein E mimetic peptide on diffuse brain injury. Apolipoprotein E mimetic peptide was administered into the caudal vein of rats with diffuse brain injury before and after injury. We found that apo-lipoprotein E mimetic peptide signiifcantly decreased the number of apoptotic neurons, reduced extracellular signal-regulated kinase1/2 phosphorylation, down-regulated Bax and cytochrome c expression, decreased malondialdehyde content, and increased superoxide dismutase activity in a dose-dependent manner. These experimental ifndings demonstrate that apolipoprotein E mimetic peptide improves learning and memory function and protects against diffuse brain injury-induced apoptosis by inhibiting the extracellular signal-regulated kinase1/2-Bax mito-chondrial apoptotic pathway.

Effect of bilobalide B on cholinergic hippocampal neurons exposed to cholesterol and apolipoprotein E4

BACKGROUND： Extracts of ginkgo biloba leaves have been reported to improve nerve function and activity in Alzheimer＇s disease, which is associated with reduced secretion of cholinergic neurotransmitter in hippocampal neurons. OBJECTIVE： To validate the protective effect of bilobalide B against in vitro injury of cholinergic neurons of the hippocampus induced by combined cholesterol and apoE4 DESIGN, TIME AND SETTING： This randomized, controlled animal experiment was performed in the Pathology Laboratory, Tianjin University of Traditional Chinese Medicine from July 2003 to July 2006. MATERIALS： Neonatal Wistar rats, 1-day-old, both male and female, and mean body mass of 5 g were selected for this study. Cholesterol and apolipoprotein E4 （apoE4） were purchased from Sigma Company （USA）, bilobalide B was purchased from Tianjin Zhongyi Pharmaceutical Factory, batch number 20050312. METHODS： Hippocampal neurons were divided into three groups： a normal control group （routinely added media）, a model group （exposed to media containing 40 mg/L cholesterol and 30 mg/L apoE4 for 24 hours） and a bilobalide B group （exposed to media containing 160 mg/L bilobalide B for 16 hours, and then with addition of 40 mg/L cholesterol and 30 mg/L apoE4 for an additional 24 hours）. MAIN OUTCOME MEASURES： Levels of acetylcholine （ACh） and activity of acetylcholinesterase （ACHE） and choline acetyltransferase （CHAT） in hippocampal neurons were determined by microdosage hydroxylamine colorimetry, hydroxylamine colorimetry and radiological chemistry, respectively. RESULTS： The ACh level was significantly lower in the model group than that in the normal control group （P 〈 0.01）, while it was markedly higher in the bilobalide B group than in the model group （P 〈 0.05）. Activity of AChE was significantly decreased in the model group compared with the normal control group （P 〈 0.05）. However, there was no significant difference between the model group and the bilobalide B group （P 〉 0.05）. Activity of ChAT was significantly lower in the model group than in the normal control group （P 〈 0.01）, while the activity was significantly higher in the bilobalide B group than in the model group （P 〈 0.05）. CONCLUSION： Bilobalide B can enhance the ACh level of hippocampal neurons damaged by combined cholesterol and apoE4, by promoting the synthesis, but not the degradation, of ACh.

Association of apolipoprotein E-219T>G promoter polymorphism with primary open angle glaucoma in Turkish population

AIM:To investigate the association between apolipoprotein E(APOE)-219 T>G promoter polymorphism and primary open angle glaucoma(POAG).METHODS:Patients and healthy subjects were genotyped with polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP).Genotype/allele frequencies were compared between 122 healthy subjects and in 75 POAG patients using Chi-square test.RESULTS:Although the frequency of APOE-219 GG genotype was higher in POAG group(13.3%)than in control group(6.6%),this finding was not statistically significant(P=0.09).In glaucoma patients carrying GG genotype,mean linear C/D ratio was higher and progression was more compared to glaucoma patients with GT genotype.CONCLUSION:APOE-219 T>G polymorphism does not seem to be a risk factor for the presence of glaucoma,but might play a role in deterioration of the disease,which needs further evaluation.

Apolipoprotein E polymorphism in northern Chinese elderly patients with coronary artery disease

Background and objective Apolipoprotein E is a constituent of lipoproteins with considerable variation due to cysteine-arginine exchanges.We investigated the relationship between apo E gene polymorphism and the occurrence of coronary artery disease(CAD)in the older population of northern China.Methods The distribution of the HhaI polymorphisms of the apolipoprotein E gene was determined among 55 patients with CAD(CAD group),which was compared with that of 36 elderly subjects without CAD(control group).Results Genotype distributions at both sites(apo E gene 112-bp and 158-bp sites)were different between the CAD and control groups.The CAD group had lower apolipoprotein E'ε2'frequencies than the control group(P<0.05).Conclusion Individuals with apolipoprotein E'ε_(2)'are likely to have a reduced risk of developing coronary artery disease as demonstrated by elderly subjects in Northern China.

Apolipoprotein E polymorphism influences orthotopic liver transplantation outcomes in patients with hepatitis C virus-induced liver cirrhosis

BACKGROUND Hepatitis C virus(HCV)infection is responsible for a chronic liver inflammation,which may cause end-stage liver disease and hepatocellular carcinoma.Apolipoprotein E(protein:ApoE,gene:APOE),a key player in cholesterol metabolism,is mainly synthesized in the liver and APOE polymorphisms may influence HCV-induced liver damage.AIM To determine whether APOE alleles affect outcomes in HCV-infected patients with liver cirrhosis following orthotopic liver transplantation(OLT).METHODS This was a cohort study in which 179 patients,both genders and aged 34-70 years,were included before or after(up to 10 years follow-up)OLT.Liver injury severity was assessed using different criteria,including METAVIR and models for endstage liver disease.APOE polymorphisms were analyzed by quantitative real-time polymerase chain reaction.RESULTS The APOE3 allele was the most common(67.3%).In inflammation severity of biopsies from 89 OLT explants and 2 patients in pre-transplant,the degree of severe inflammation(A3F4,0.0%)was significantly less frequent than in patients with minimal and moderate degree of inflammation(≤A2F4,16.2%)P=0.048,in patients carrying the APOE4 allele when compared to non-APOE4.In addition,a significant difference was also found(≤A2F4,64.4%vs A3F4,0.0%;P=0.043)and(A1F4,57.4%vs A3F4,0.0%;P=0.024)in APOE4 patients when compared to APOE3 carriers.The fibrosis degree of the liver graft in 8 of 91 patients and the lack of the E4 allele was associated with more moderate fibrosis(F2)(P=0.006).CONCLUSION Our results suggest that the E4 allele protects against progression of liver fibrosis and degree of inflammation in HCV-infected patients.

Association between apolipoprotein E promoter-219G/T polymorphism and total cholesterol level in patients with Alzheimer disease

BACKGROUND: Many researches have suggested that apolipoprotein E (APOE) and total cholesterol metabolism are closely related with dementia. In the supposed theory, 219 site of APOE promoter region is near gene coding region, so its polymorphism may result in the abnormality of APOE gene and protein expression, and finally lead to dementia. OBJECTIVE: To observe the association between APOE promoter-219G/T polymorphisms with serum total cholesterol in patients with Alzheimer disease, and compare it with non-dementia people. DESIGN: Case-control, comparative observation. SETTING: Department of Neurology, Fengtian Hospital of Shenyang Medical College. PARTICIPANTS: Fifty-five dementia patients including 27 males and 28 females aged (66±3) years and treated in the Department of Neurology, Fengtian Hospital were selected from January 2002 to December 2005 as the Alzheimer disease group. They all diagnosed according to the DSM-Ⅳdiagnostic criteria of Alzheimer disease instituted by American Psychiatry Association in 1994. Meanwhile, 44 none-dementia patients including 21 males and 23 females aged (66±3) years were selected from other clinical departments of Fengtian Hospital as control group. All the participants were informed the detection and agreed. METHODS: Genomic DNA was extracted from the peripheral blood of all subjects, then 'NEST'PCR, DNA sequence and enzyme digestion were adopted to detect the expression of APOE promoter-219 polymorphism, following by biomedical statistics analysis based on the clinical total cholesterol level. MAIN OUTCOME MEASURES: Polymorphism of APOE promoter-219 G/T and total cholesterol level. RESULTS: All 55 dementia patients and 44 non-dementia ones were involved in the result analysis. ①Allele and genotype frequency: The T allele frequency of the Alzheimer disease group was significantly higher than that in the control group [88.2% (97/110), 54.5% (48/88)], while G allele frequency was remarkably lower than that in the control group [11.8%(13/110), 45.5%(40/88), χ2=8.2, P < 0.01]. The TT allele frequency of the Alzheimer disease group was significantly higher than that in the control group [76% (42/55), 48% (21/44)], while GT+GG allele frequency was remarkably lower than that in the control group [24%(13/55), 52%(23/44), χ2=8.7, P < 0.01]. ②Total cholesterol level: The level of the TT genotype patients in the Alzheimer group was obviously higher than that in GT+GG genotype patients (t =2.46, P < 0.05); the cholesterol level in the two genotypes of the control group was similar (P > 0.05). CONCLUSION: TT genotype and allele T in the APOE promoter-219 polymorphisms are the sensitive gene, and genotype TT has a relationship with the increase of total cholesterol level.

Effects of simvastatin on early oxidative stress and endothelial function in apolipoprotein E-deficient mice

Objective： To investigate the mechanisms that Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A（HMG-CoA） reductase inhibitor, plays an important role in primary prevention of atherosclerosis independently of its lipid-lowering effect in Apolipoprotein E-deficient mice in the early stage of atherosclerosis. Methods： Twenty-four 6-week old male apoE-deficient mice were randomly divided into two groups：control group（normal saline） and treatment group[simvastatin（5 mg/（kg · d））]. Simvastatin was administered to treatment group mice by gavage and the same volume of normal saline was administered to control group mice by the same method for 2 or 4 weeks. Total cholesterol（TC）, super-oxide dismutase（SOD）, malondialdehyde（MDA） and serum nitric oxide（NO） were measured by biochemical analysis. Results： There was no significant difference in serum TC between control and treatment groups. Compared with the control＇ s, the effects of simvastatin were more significant in decreasing serum MDA level（P 〈 0.01 vs control＇ s at 2-week; P 〈 0.006 vs control＇ s at 4-week）, increasing serum SOD level（P 〈 0.03 vs control＇ s at 2-week; P 〈 0.003 vs control＇ s at 4-week） and NO level （P 〈 0.01 control＇ s at 2-week; P 〈 0.001 vs control＇ s at 4-week） either at 2 or 4 weeks. Conclusion： Simvastatin attenuates oxidative stress and protects endothelial function by the mechanisms of decreasing serum MDA level, increasing serum SOD level and NO level, which were inconsistent with its cholesterol-lowering effect. It may play an important role in primary（if not all） prevention of atherosclerosis and might be independent of lipid-regulation mechanism.

Cognitive function correlations with apolipoprotein Eε4 single nucleotide polymorphism in 1000 elderly patients following general anesthesia A randomized controlled study

BACKGROUND： Cognitive dysfunction occurs in elderly patients following general anesthesia, and this might be associated with genetics. Studies have shown that the ε4 allele gene is closely associated with senile dementia. OBJECTIVE： To compare and analyze the correlations between cognitive dysfunction and single nucleotide polymorphism of apolipoprotein E （ApoE） following inhalation or intravenous anesthesia. DESIGN, TIME AND SETTING： A randomized, controlled study was performed. The patients were recruited from the Department of Anesthesia, Second Affiliated Hospital, Medical College, Xi＇an Jiaotong University, China between May 2005 and December 2008. Genetic analyses were conducted at the Departments of Neuroanatomy and Forensic Medicine, Medical Corlege, Xi＇an Jiaotong University, China. PARTICIPANTS： A total of t 000 patients of ASA I-II grade, without genetic connection, were enrolled in this study, comprising 520 males and 480 females, aged （70.1± 4.6） years and weighing （57.3 ± 7.5） kg. No patients suffered from cognitive dysfunction. METHODS： The patients were equally and randomly divided into intravenous anesthesia and gas anesthesia groups. Total intravenous anesthesia and inhaled anesthesia were used. Genomic DNA from whole blood was extracted. The ApoE gene was amplified by PCR. Restriction fragment length polymorphism of ApoE gene was analyzed. Cognitive function was evaluated by Mini-Mental State Examination （MMSE）. Patients scoring 〈 25 points were diagnosed with cognitive dysfunction. MAIN OUTCOME MEASURES： Correlation of ApoE gene frequency and ApoE ε 4 allele to MMSE scores was measured. RESULTS： MMSE scores in patients from the gas anesthesia group significantly decreased 3 days after surgery, compared with the intravenous anesthesia group. The proportion of patients that scored 〈 25 points was significantly greater in the gas anesthesia group compared with the intravenous anesthesia group 3 days after surgery. Reduced MMSE scores closely correlated with expression of the ApoE ε 4 allele in the gas anesthesia group （odds ratio = 2.83; 95% confidence interval was 1.25-6.39, P 〈 0.05）. However, decreased MMSE scores did not closely correlated with expression of the ApoE ε 4 allele in the intravenous anesthesia group （odds ratio = 0.96; 95% confidence interval was 0.37-2.39, P 〉 0.05）. CONCLUSION： Results demonstrated a correlation between cognitive dysfunction and ApoE single nucleotide polymorphism in elderly patients after gas anesthesia. However, no relationship between cognitive dysfunction and ApoE single nucleotide polymorphism was determined in elderly patients following intravenous anesthesia. Therefore, elderly patients, especially those expressing the ApoE ε4 gene, should be cautiously exposed to gas anesthesia.

Alterations in amyloid beta-protein and apolipoprotein E in cerebrospinal fluid after subarachnoid hemorrhage

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.