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1.
Postgrad Med ; 131(7): 501-508, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31483196

RESUMO

Objectives: Aiginition Longitudinal Biomarker Investigation Of Neurodegeneration (ALBION) is a longitudinal ongoing study initiated in 2018 that takes place in the Cognitive Disorders Clinic of Aiginition Hospital of the National and Kapodistrian University of Athens. Its aim is to address several research questions concerning the preclinical and prodromal stage of Alzheimer's disease and explore potential markers for early detection, prediction, and primary prevention of dementia. Methods: We here present the design and the preliminary baseline characteristics of ALBION. The sample of our study consists of people aged over 50 who are concerned about their memory but are cognitively normal (CN) or have mild cognitive deficits. Each participant undergoes an extensive assessment including several demographic, medical, social, environmental, clinical, nutritional, neuropsychological determinants and lifestyle activities. Furthermore, we are collecting data from portable devices, neuroimaging techniques and biological samples (blood, stools, CSF). All participants are assessed annually for a period of 10 years. Results: In total, 47 participants have completed the initial evaluation up to date and are divided in two groups, CN individuals (N = 26) and MCI patients (N = 21), based on their cognitive status. The participants are, on average, 64 years old, 46.3% of the sample is male with an average of 12.73 years of education. MCI patients report more comorbidities and have a lower score in the MMSE test. Regarding APOE status, 2 participants are ε4 homozygotes and 10 ε4 heterozygotes. CSF analyses (Aß42, Τ-tau, P-tau) revealed no differences between the two groups. Conclusion: The ALBION study offers an opportunity to explore preclinical dementia and identify new and tailored markers, particularly relating to lifestyle. Further investigation of these populations may provide a wider profile of the changes taking place in the preclinical phase of dementia, leading to potentially effective therapeutic and preventive strategies.


Assuntos
Doença de Alzheimer/prevenção & controle , Disfunção Cognitiva/metabolismo , Prevenção Primária , Sintomas Prodrômicos , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteínas E/genética , Biomarcadores , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/fisiopatologia , Diagnóstico Precoce , Eletroencefalografia , Feminino , Neuroimagem Funcional , Grécia , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Dados Preliminares , Proteínas tau/líquido cefalorraquidiano
2.
J Assoc Physicians India ; 67(7): 43-48, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31559768

RESUMO

Aim: To delineate the genetic differences in polymorphism of the APOE and D2S439 marker genes for patients with and without rheumatoid arthritis and to study the distribution frequency of the prevalent alleles of these genes in clinically defined sub groups of patients/controls of Indian origin, specifically and their correlation with severity of disease using DAS score. Material and Methods: This is a case control study where peripheral blood samples 160 cases and 150 controls were collected. Results: We evaluated the association of the tetra nucleotide repeat microsatellite marker D2S439 lying at 231.27cM position on the q arm of chromosome-2. The alleles of this marker ranged in size from 163bp-203bp in PCR product length corresponding to 5-15 (CTAT)n tetra repeats. The allele frequencies for this marker in the North Indian population are different from the CEPH populations. The longer alleles, >199bp (=14 or 15 CTAT repeats) were not observed. The genotypes after bimodal distribution differ significantly among cases and controls (p=0.003). Statistically significant difference was seen between cases and controls for ≥(CTAT) 10 longer allele which was more prevalent in the adult RA cases than in controls. Severity of RA was defined by a DAS28 score of >6 on a scale of ten. No significant association was seen with the APOE polymorphism and disease severity. Conclusion: The long allele of D2S439 marker representing an expansion of the CTAT, tetranucleotide repeat doubles an individual's the risk for developing RA.


Assuntos
Apolipoproteínas E/genética , Artrite Reumatoide , Repetições de Microssatélites , Adulto , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de Doença
3.
Medicine (Baltimore) ; 98(30): e16604, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31348306

RESUMO

Amnestic mild cognitive impairment (aMCI) is a transitional stage between normal aging and Alzheimer disease (AD), and is associated with an increased risk of AD. Many studies have shown that apolipoprotein E epsilon 4 (APOE ε4) genotype is a major genetic predictor of AD progression, especially in patients with aMCI. However, the application of APOE genotyping in the diagnosis of MCI progressing to AD is limited by its low sensitivity and specificity, which often leads to high false-positive rate. The aim of this study was to evaluate serum brain-derived neurotrophic factor (BDNF) and hippocampal volume as predictors of aMCI to AD transition in APOE ε4 genotype patients.A total of 178 subjects were diagnosed with aMCI. The patients with aMCI that progressed to AD within 2 years were included in the MCI-AD group (n = 86), those maintaining an aMCI diagnosis after 2 years were placed in the MCI-MCI group (n = 92), and neurologically healthy age-matched individuals were set as controls (n = 90). APOE genotypes were determined. Blood samples from all subjects were drawn at baseline, 12 months, and 24 months for serum BNDF assessments. Hippocampal delineations were monitored by magnetic resonance imaging.Compared to control group, aMCI-AD patients (the patients with aMCI that progressed to AD within 2 years) exhibited worse performance on cognitive and neuropsychological batteries. Meanwhile, we found that aMCI-AD patients were associated with abnormally low serum BDNF level and greater hippocampal volume loss than MCI-MCI patients (patients maintaining an aMCI diagnosis after 2 years). Moreover, patients with aMCI who were carriers of APOE ε4 showed a notable decrease in serum BDNF and a significant reduction in hippocampal volume, especially in those who progressed to AD.The present study demonstrates that aMCI that evolves into AD in patients with the APOE ε4 genotype may be predicted by hippocampal volume and serum BDNF.


Assuntos
Doença de Alzheimer/diagnóstico , Apolipoproteínas E/genética , Fator Neurotrófico Derivado do Encéfalo/sangue , Disfunção Cognitiva/diagnóstico , Hipocampo/anatomia & histologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Biomarcadores , Disfunção Cognitiva/genética , Feminino , Humanos , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade
4.
Medicine (Baltimore) ; 98(28): e16405, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305452

RESUMO

Our study investigated the association of five genes with MCI in the Xinjiang Uygur population in China. In addition, we also analyzed the association between APOE methylation and MCI.Forty-three MCI and 125 controls were included in the present study. Genotyping was done by Sanger sequencing. DNA methylation assay was done using quantitative methylation-specific polymerase chain reaction (qMSP).The distribution of HMGCR rs3846662 allele frequencies was significantly different between the MCI group and the control group (P = .04), especially in women (P = .032). Subgroup analysis showed that there was a statistically significant association of HMGCR rs3846662 with MCI in the non-APOE ε4 group (P = .024), especially in the females with non-APOE ε4. Similarly, HMGCR rs3846662 genotype and allele frequency in the ApoE E2 protein group were significantly different in the MCI group and the control group (genotype P = .021; allele P = .007). In addition, SIRT1 rs7895833 genotype frequency in the APOE ε4 group was found to be significantly different between the MCI and the control group (P = .005). We also observed a significant association of SIRT1 rs7895833 with MCI in the ApoE E4 protein subgroup (P = .005). In addition, APOE methylation levels were significantly different between the MCI group and the control group (P = .021), especially in men (P = .006). Subgroup analysis showed that APOE methylation levels were significantly associated with MCI in the non-APOE ε4 group (P = .009), especially in men (P = .015).This study found a significant association of HMGCR rs3846662 with MCI in females independent of APOE ε4. In contrast, we revealed that the association of SIRT1 rs7895833 with MCI was dependent on with APOE ε4. We also showed that hypermethylation of APOE in MCI was independent of APOE ε4.


Assuntos
Apolipoproteínas E/genética , Transtornos Cognitivos/genética , Transtornos Cognitivos/metabolismo , Metilação de DNA , Hidroximetilglutaril-CoA Redutases/genética , Sirtuína 1/genética , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino
5.
Gene ; 715: 144011, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31357022

RESUMO

BACKGROUND: An association between Apolipoprotein E (Apo E) alleles and genotypes and diabetic nephropathy (DN) was suggested, but with inconsistent results. We tested the relationship between serum lipids, Apo E alleles and genotypes with type 2 diabetes (T2DM), and DN pathogenesis. METHODS: Study subjects comprised 1389 normoglycemic controls, and 1422 T2DM patients, of whom 825 were normoalbuminuric (DWN), and 597 presented with nephropathy (DN). RESULTS: Significantly lower Apo ε2, and higher Apo ε4 allele frequencies was seen among T2DM patients than controls. Significantly higher frequency of ε3/ε4, and lower frequencies of ε3/ε3, ε2/ε3, and ε4/ε4 carriers was seen among T2DM cases. Apo ε2-carrying individuals were more frequently found in controls than in patients, while significantly higher frequency of ε4-carrying genotypes was seen in T2DM cases. Significantly higher ε2, and lower ε3 allele frequencies were noted for DN group compared to DWN group. Significantly higher frequency of ε2-containing ε2/ε3 and ε2/ε4, and lower frequencies of ε3/ε3 carriers was seen among DN cases. Apo ε3/ε3 was associated with higher total cholesterol, LDL-cholesterol, and triglyceride levels in DN patients, and significantly higher triglyceride levels were seen in ε2/ε3-carrying DN patients. Logistic regression analysis confirmed the association of Apo ε3-containing ε3/ε3, ε2/ε3, and ε3/ε4, and Apo ε2-containing ε2/ε4 with DN, after controlling for key covariates. CONCLUSION: The results of this case-control study provide evidence that the ε2 and ε3 alleles of APOE modify lipid profile, and constitute independent risk factors of DN in type 2 diabetes. The molecular mechanisms underlying this risk is discussed.


Assuntos
Alelos , Apolipoproteínas E/genética , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Frequência do Gene , Predisposição Genética para Doença , Idoso , Apolipoproteínas E/sangue , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Nefropatias Diabéticas/sangue , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Fatores de Risco
6.
Environ Pollut ; 252(Pt B): 1455-1463, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31265956

RESUMO

Circadian rhythm is believed to play important roles in atherosclerosis. The gut microbiota is found to be closely related to atherogenesis, and shows compositional and functional circadian oscillation. However, it's still unclarified whether circadian clock and intestinal microbiota are involved in the progression of atherosclerosis induced by environmental pollutant acrolein. Herein, patients with atherosclerosis showed higher MMP9, a promising biomarker for atherosclerosis, and lower Bmal1 and Clock expression in the plasma. Interestingly, acrolein exposure contributed to the increased MMP9, decreased Clock and Bmal1, and activated MAPK pathways in human umbilical vein endothelial cells (HUVECs). We found that knockdown of Clock or Bmal1 lead to upregulation of MMP9 in HUVECs, and that Clock and Bmal1 expression was elevated while MAPK pathways were blocked. Atherosclerotic apolipoproteinE-deficient mice consumed a high-fat diet were used and treated with acrolein (3 mg/kg/day) in the drinking water for 12 weeks. Upregulation of MMP9, and downregulation of Clock and Bmal1 were also observed in plasma of the mice. Besides, acrolein feeding altered gut microbiota composition at a phylum level especially for an increased Firmicutes and a decreased Bacteroidetes. Additionally, gut microbiota showed correlation with atherosclerotic plaque, MMP9 and Bmal1 levels. Therefore, our findings indicated that acrolein increased the expression of MMP9 through MAPK regulating circadian clock, which was associated with gut microbiota regulation in atherosclerosis. Circadian rhythms and gut microbiota might be promising targets in the prevention of cardiovascular disease caused by environmental pollutants.


Assuntos
Fatores de Transcrição ARNTL/sangue , Aterosclerose/patologia , Proteínas CLOCK/sangue , Ritmo Circadiano/fisiologia , Microbioma Gastrointestinal/fisiologia , Metaloproteinase 9 da Matriz/metabolismo , Fatores de Transcrição ARNTL/genética , Acroleína , Adulto , Animais , Apolipoproteínas E/genética , Aterosclerose/induzido quimicamente , Proteínas CLOCK/genética , Linhagem Celular , Relógios Circadianos/fisiologia , Dieta Hiperlipídica , Regulação para Baixo , Feminino , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Knockout
7.
Gene ; 711: 143948, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31255737

RESUMO

The incidence of atherosclerosis is greatly increased, which becomes the leading cause for the death and disability worldwide. Endothelial cells dysfunction plays a substantial role in the pathogenesis of atherosclerosis. MicroRNA-148a-3p (miR-148a-3p) and circular RNA 0003575 (circ_0003575) modulated lipid metabolism and proliferative function of endothelial cells, respectively. However, the role of them in modulation of endothelial cell function and progression of atherosclerosis remains unknown. Endothelial cells were isolated from the aorta of Apoe-/- mice. miR-148a-3p in atherosclerosis patients and healthy controls were measured by qRT-PCR. Overexpression and knockdown of miR-148a-3p in endothelial cells were established. The proliferation, migration and apoptosis of endothelial cells were measured by MTT, Transwell, and fluorescence microscope, respectively. Online software (miRWalk 2.0 and RegRNA2.0) and databases (miRWalk, miRanda, RNA22, and Targetscan) were used to predict potential target genes of miR-148a-3p and circ_0003575. The expression of target genes was detected through western blotting. The expression of miR-148a-3p was significantly upregulated in patients with atherosclerosis as relative to healthy people. Overexpression of miR-148a-3p exhibited stimulatory effects on endothelial cell proliferation and migration and inhibited programmed cell death. Six intersection target genes, c-MAF, FOXO4, FOXO3, MITF, ETV7, and CRX, were predicted between miR-148a-3p and circ_0003575. The opposite effects of circ_0003575 and miR-148a-3p on the expression of FOXO4 and FOXO3, which are essential for lipid metabolism. We demonstrate that miR-148a-3p suppresses FOXO4 and FOXO3 expression via interruption of circ_0003575 function, which in turn impairs the proliferative and migratory function of endothelial cells, eventually exacerbating the atherosclerosis.


Assuntos
Apolipoproteínas E/deficiência , Aterosclerose/genética , Células Endoteliais/citologia , Proteína Forkhead Box O3/metabolismo , MicroRNAs/genética , RNA/genética , Fatores de Transcrição/metabolismo , Regulação para Cima , Animais , Apolipoproteínas E/genética , Apoptose , Aterosclerose/metabolismo , Estudos de Casos e Controles , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Proteína Forkhead Box O3/genética , Redes Reguladoras de Genes , Humanos , Metabolismo dos Lipídeos , Camundongos , Fatores de Transcrição/genética
8.
Artigo em Chinês | MEDLINE | ID: mdl-31245949

RESUMO

OBJECTIVE: To evaluate the effects of 12 weeks high intensity interval training(HIIT) on serum lipids profile in patients with dyslipidemia of different apolipoprotein E(ApoE) genotypes. METHODS: Eighty-eight patients with dyslipidemia were screened by fasting blood lipid as subjects. Apolipoprotein E genotypes were detected in oral mucosa of subjects. Serum lipids before and after 12 weeks high intensity interval training were measured to analysis the effect of high intensity interval training on serum lipids. RESULTS: Five genotypes were detected in 88 cases of dyslipidemia. The distributions were ApoE3/3>ApoE3/4>ApoE2/3>ApoE2/2>ApoE2/4,and allele ε3>ε2=ε4. Before exercise intervention, the level of total cholesterol in patients with ε4 allele was significant higher than those in patients with ε2 and ε3 (P<0.01), low density lipoprotein cholesterol in patients with ε4 was significant higher than that of patients with ε2 (P<0.05), and the other indexes had no significant difference among the groups (P> 0.05). After 12 weeks high intensity interval training, the levels of total cholesterol, triglyceride and low density lipoprotein cholesterol were decreased significantly ,while the level of high density lipoprotein cholesterol was increased in those patients with ε3 genotype. For those individuals with ε4 genotype , their serum levels of total cholesterol and low density lipoprotein cholesterol were reduced after 12 weeks high intensity interval training , but there was no changes in serum levels of triglyceride and high density lipoprotein cholesterol. For those individuals with ε2 genotype, there was no significant improvement in serum lipids after 12 weeks high intensity interval training interventions. CONCLUSION: The polymorphisms of apolipoprotein E gene resulted in different effects of exercise interventions on serum lipids of dyslipidemia. Twelve weeks high intensity interval training can be used as an intervention method to regulate serum lipids of dyslipidemia with ε3 and ε4 alleles.


Assuntos
Apolipoproteínas E , Dislipidemias , Treinamento Intervalado de Alta Intensidade , Lipídeos , Apolipoproteínas E/genética , Dislipidemias/genética , Dislipidemias/terapia , Genótipo , Humanos , Lipídeos/sangue
9.
JAMA ; 321(23): 2316-2325, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31211344

RESUMO

Importance: A National Institute on Aging and Alzheimer's Association workgroup proposed a research framework for Alzheimer disease in which biomarker classification of research participants is labeled AT(N) for amyloid, tau, and neurodegeneration biomarkers. Objective: To determine the associations between AT(N) biomarker profiles and memory decline in a population-based cohort of individuals without dementia age 60 years or older, and to determine whether biomarkers provide incremental prognostic value beyond more readily available clinical and genetic information. Design, Setting, and Participants: Population-based cohort study of cognitive aging in Olmsted County, Minnesota, that included 480 nondemented Mayo Clinic Study of Aging participants who had a clinical evaluation and amyloid positron emission tomography (PET) (A), tau PET (T), and magnetic resonance imaging (MRI) cortical thickness (N) measures between April 16, 2015, and November 1, 2017, and at least 1 clinical evaluation follow-up by November 12, 2018. Exposures: Age, sex, education, cardiovascular and metabolic conditions score, APOE genotype, and AT(N) biomarker profiles. Each of A, T, or (N) can be abnormal (+) or normal (-), resulting in 8 AT(N) profiles. Main Outcomes and Measures: Primary outcome was a composite memory score measured longitudinally at 15-month intervals. Analyses measured the associations between predictor variables and the memory score, and whether AT(N) biomarker profiles significantly improved prediction of memory z score rates of change beyond a model with clinical and genetic variables only. Results: Participants were followed up for a median of 4.8 years (interquartile range [IQR], 3.8-5.1) and 44% were women (211/480). Median (IQR) ages ranged from 67 years (65-73) in the A-T-(N)- group to 83 years (76-87) in the A+T+(N)+ group. Of the participants, 92% (441/480) were cognitively unimpaired but the A+T+(N)+ group had the largest proportion of mild cognitive impairment (30%). AT(N) biomarkers improved the prediction of memory performance over a clinical model from an R2 of 0.26 to 0.31 (P < .001). Memory declined fastest in the A+T+(N)+, A+T+(N)-, and A+T-(N)+ groups compared with the other 5 AT(N) groups (P = .002). Estimated rates of decline in the 3 fastest declining groups were -0.13 (95% CI, -0.17 to -0.09), -0.10 (95% CI, -0.16 to -0.05), and -0.10 (95% CI, -0.13 to -0.06) z score units per year, respectively, for an 85-year-old APOE ε4 noncarrier. Conclusions and Relevance: Among older persons without baseline dementia followed for a median of 4.8 years, a prediction model that included amyloid PET, tau PET, and MRI cortical thickness resulted in a small but statistically significant improvement in predicting memory decline over a model with more readily available clinical and genetic variables. The clinical importance of this difference is uncertain.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Apolipoproteínas E/genética , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Imagem por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Estudos de Coortes , Demência , Progressão da Doença , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
10.
Adv Exp Med Biol ; 1128: 85-101, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31062326

RESUMO

Although the mechanisms by which Alzheimer's disease (AD) occurs remains unclear, it is widely accepted that both genetic and nongenetic components contribute to the pathogenesis of AD, especially the sporadic form of the disease. Nongenetic risk factors include diabetes and dyslipidemia, which are associated with impaired glucose and lipid metabolism, respectively. Apolipoprotein E (ApoE), one of the major lipid carriers in the brain, is the strongest genetic risk factor for late-onset AD. Several studies indicate that ApoE isoforms differentially affect not only lipid metabolism but also glucose metabolism or related pathways, suggesting that these risk factors contribute to the pathogenesis of AD through some common mechanisms. In this chapter, we discuss the roles of ApoE, lipids, and glucose in the pathogenesis of AD by considering their potential interactions.


Assuntos
Doença de Alzheimer/patologia , Apolipoproteínas E/genética , Glucose/metabolismo , Metabolismo dos Lipídeos , Doença de Alzheimer/genética , Encéfalo , Humanos
11.
Gene ; 707: 212-215, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31102717

RESUMO

BACKGROUND: Alzheimer's disease is a progressive, irreversible neurodegenerative disorder characterized by loss of memory and cognitive skills. More than 90% of cases are sporadic and have later age of onset. Many studies have shown a genetic predisposition for late onset Alzheimer's disease (LOAD). The most studied genetic predisposition factor is apolipoprotein E gene besides other susceptibility genes involved in vascular pathologies, homocysteine metabolism, and neuronal growth and differentiation such as methylenetetrahydrofolate reductase (MTHFR), angiotensin-converting enzyme (ACE), APOB and brain derived neurotrophic factor (BDNF). METHODS: In this study Factor V Leiden (G1691A) and H1299R, prothrombin G20210A, Factor XIII V34L, B-fibrinogen -455G>A, PAI-1 5G/4G, HPA1 b/a, MTHFR C677T, MTHFR A1298C, APOE, ACE I/D, BDNF C270T and G196A polymorphisms were evaluated in 100 LOAD patients and 100 age matched healthy controls. RESULTS: APOE4 allele, MTHFR CCA1298C and BDNF TTC270T genotypes were significantly higher in LOAD patients compared to the control group (p < 0.001, p = 0.04, p = 0.03, respectively). There were no significant associations between other genotypes and allele frequencies. Mini-Mental State Examination (MMSE) scores and age at onset of the patients were also evaluated for each and combined genotypes. Age at onset was significantly lowered by about approximately 4 and 5 years in patients carrying BDNF TTC270T and MTHFR TTC677T genotypes, respectively. CONCLUSION: APOE, MTHFR A1298C and BDNF C270T polymorphisms may be associated with LOAD and BDNF and MTHFR alleles may play a role in the age at onset of the LOAD.


Assuntos
Doença de Alzheimer/genética , Apolipoproteínas E/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Mutação , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
12.
Gene ; 706: 154-161, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31054363

RESUMO

PURPOSE: To evaluate the association of the presence, invasiveness, hormonal activity and recurrence of pituitary adenoma (PA) with ApoE genotypes and alleles. MATERIALS AND METHODS: Our study group included 142 patients with PA and the control group included 256 healthy individuals. The genotyping of ApoE (rs7412 and rs429358) was performed using a real-time PCR method. RESULTS: After statistical analysis we found that ApoE genotype E2/E3 was associated with 2.6-fold increased odds of active PA (OR = 2.609; 95%CI: 1.380-4.932; p = 0.003), while the presence of ApoE E3/E3 decreased odds of active PA by 65% (OR = 0.343; 95%CI: 0.205-0.575; p < 0.001). The frequency of the allele ε3 was lesser in the PA group (74.3% vs. 83%, p = 0.003) when compared to controls but it was statistically significantly more frequent in the invasive PA than in the noninvasive PA subgroup (80.4% vs. 65.5%, p = 0.005). The ApoE E2/E4 genotype was more frequent in the noninvasive PA subgroup (10.3% vs. 0%, p = 0.003) than in the invasive PA subgroup. The ApoE E4/E4 genotype was more frequent in the recurrent than in the non-recurrent PA subgroup (6.6% vs. 0%, p = 0.006). No associations between ApoE polymorphisms and Ki-67 labelling index were found. CONCLUSION: The ApoE E2/E3 genotype is associated with the presence of PA while the ApoE genotype E2/E4 is associated with noninvasive PA development. The allele ε3 could possibly have a protective effect against PA. The genotype E4/E4 is associated with the development of recurrent PA.


Assuntos
Apolipoproteínas E/genética , Neoplasias Hipofisárias/genética , Adenoma/genética , Adulto , Idoso , Alelos , Apolipoproteínas E/fisiologia , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença , Genótipo , Haplótipos/genética , Humanos , Lituânia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
13.
J Clin Neurosci ; 66: 83-86, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31126849

RESUMO

Cervical spondylotic myelopathy (CSM) is a progressive degenerative spine disease. It is not clear why certain patients develop symptomatic myelopathy whereas others do not, even in the presence of radiographic features of cervical stenosis. Genetic predisposition has been suggested, supported by familial occurrence of CSM. In this study we explored the demographic and radiographic features of CSM in Indian population and studied the association between polymorphisms in interleukin18RAP and apo-lipoprotein genes in CSM. A total of 100 CSM patients and 100 healthy control subjects were included in this study. Genotyping of APOE (rs7412 and rs429358) and IL18RAP (rs1420106 and rs917997) gene polymorphisms was performed by Taqman allelic discrimination assay. Comparison of allelic frequencies, ε2 versus ε3 (OR = 4.4, 95%CI = 1.23-15.73, P = 0.002) and ε2 versus ε4 (OR = 6.67, 95%CI = 1.58-28.04, P = 0.009) showed a statistically significant association for the risk of CSM. There was no significant association between different genotypes with sex, T2 signal intensity change and Nurick grade. Only patients having multiple level cervical prolapsed intervertebral disc (PIVD) on MRI, had a higher proportion of the ε2 allele as compared to controls (p = <0.0001). No significant association was found between IL18RAP gene polymorphisms (rs1420106 and rs917997) with the risk of CSM. ε2 allele was associated with the risk of CSM in Indian population. There was no significant association between the two single nucleotide polymorphisms (SNPs) of IL18RAP gene with risk of CSM.


Assuntos
Apolipoproteínas E/genética , Subunidade beta de Receptor de Interleucina-18/genética , Polimorfismo de Nucleotídeo Único , Espondilose/genética , Adulto , Alelos , Vértebras Cervicais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
14.
Int J Mol Sci ; 20(9)2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31052389

RESUMO

Apolipoprotein E (apoE), a key lipid transport protein in the brain, is predominantly produced by astrocytes. Astrocytes are the most numerous cell type in the brain and are the main support network for neurons. They play a critical role in the synthesis and delivery of cholesterol in the brain. Humans have three common apoE isoforms, apoE2, apoE3 and apoE4, that show a strong genotype effect on the risk and age of onset for sporadic and late onset forms of Alzheimer's disease (AD). Carriers of an ε4 allele have an increased risk of developing AD, while those with an ε2 allele are protected. Investigations into the contribution of apoE to the development of AD has yielded conflicting results and there is still much speculation about the role of this protein in disease. Here, we review the opposing hypotheses currently described in the literature and the approaches that have been considered for targeting apoE as a novel therapeutic strategy for AD. Additionally, we provide our perspective on the rationale for targeting apoE and the challenges that arise with respect to "drug-ability" of this target.


Assuntos
Doença de Alzheimer/metabolismo , Apolipoproteínas E/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Animais , Apolipoproteínas E/química , Apolipoproteínas E/genética , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Humanos , Terapia de Alvo Molecular , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico
15.
Eur J Med Chem ; 176: 129-134, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31102933

RESUMO

Cardiovascular disease is the leading cause of mortality and morbidity worldwide. Atherosclerosis accounts for 50% of deaths in western countries. This multifactorial pathology is characterized by the accumulation of lipids and inflammatory cells within the vascular wall, leading to plaque formation. We describe herein the synthesis of a PCTA-based 68Ga3+ chelator coupled to a phospholipid biovector 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), which is the main constituent of the phospholipid moiety of High-Density Lipoprotein (HDL) phospholipid moiety. The resulting 68Ga-PCTA-DSPE inserted into HDL particles was compared to 18F-FDG as a PET agent to visualize atherosclerotic plaques. Our agent markedly accumulated within mouse atheromatous aortas and more interestingly in human endarterectomy carotid samples. These results support the potential use of 68Ga-PCTA-DSPE-HDL for atherosclerosis PET imaging.


Assuntos
Aterosclerose/diagnóstico por imagem , Quelantes/química , Radioisótopos de Gálio/química , Compostos Heterocíclicos com 2 Anéis/química , Fosfatidiletanolaminas/química , Compostos Radiofarmacêuticos/química , Animais , Aorta/metabolismo , Aorta/patologia , Apolipoproteínas E/genética , Artérias Carótidas/metabolismo , Artérias Carótidas/patologia , Quelantes/síntese química , Portadores de Fármacos/química , Desenvolvimento de Medicamentos , Compostos Heterocíclicos com 2 Anéis/síntese química , Humanos , Lipoproteínas HDL/química , Fígado/metabolismo , Camundongos Knockout , Miocárdio/metabolismo , Miocárdio/patologia , Fosfatidiletanolaminas/síntese química , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/síntese química
16.
J Agric Food Chem ; 67(22): 6190-6201, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31117496

RESUMO

Sesamol, an antioxidant lignan from sesame oil, possesses neuroprotective bioactivities. The present work was aimed to elucidate the systemic protective effects of sesamol on cognitive deficits and to determine the possible link between gut and brain. Wildtype and ApoE-/- mice were treated with a high-fat diet and sesamol (0.05%, w/v, in drinking water) for 10 weeks. Behavioral tests including Morris-water maze, Y-maze, and elevated plus maze tests indicated that sesamol could only improve cognitive deficits and anxiety behaviors in wildtype. Consistently, sesamol improved synapse ultrastructure and inhibited Aß accumulation in an ApoE-dependent manner. Moreover, sesamol prevented dietary-induced gut barrier damages and systemic inflammation. Sesamol also reshaped gut microbiome and improved the generation of microbial metabolites short-chain fatty acids. To summarize, this study revealed that the possible mechanism of neuroprotective effects of sesamol might be ApoE-dependent, and its beneficial effects on gut microbiota/metabolites could be translated into neurodegenerative diseases treatment.


Assuntos
Apolipoproteínas E/metabolismo , Benzodioxóis/administração & dosagem , Encéfalo/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Fenóis/administração & dosagem , Óleo de Gergelim/química , Animais , Apolipoproteínas E/genética , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/isolamento & purificação , Bactérias/metabolismo , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/microbiologia , Ácidos Graxos Voláteis/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
17.
Curr Pharm Biotechnol ; 20(5): 422-432, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30947667

RESUMO

BACKGROUND: Tanshinone IIA (Tan IIA) and Omentin-1 have a protective role in the cardiovascular system. However, if and how Tan IIA and Omentin-1 regulate cholesterol metabolism in macrophages has not been fully elucidated. OBJECTIVE: To investigate the possible mechanisms of Tan IIA and Omentin-1 on preventing macrophage cholesterol accumulation and atherosclerosis development. METHODS: The effect of Tan IIA on the protein and mRNA levels of Omentin-1 and ATP-binding cassette transporter A1 (ABCA1) in macrophages was examined by Western blot and qRT-PCR assay, respectively. Cholesterol efflux was assessed by liquid scintillation counting (LSC). Cellular lipid droplet was measured by Oil Red O staining, and intracellular lipid content was detected by high performance liquid chromatography (HPLC). In addition, the serum lipid profile of apoE-/- mice was measured by enzymatic method. The size of atherosclerotic lesion areas and content of lipids and collagen in the aortic of apoE-/- mice were examined by Sudan IV, Oil-red O, and Masson staining, respectively. RESULTS: Tan IIA up-regulated expression of Omentin-1 and ABCA1 in THP-1 macrophages, promoting ABCA1-mediated cholesterol efflux and consequently decreasing cellular lipid content. Consistently, Tan IIA increased reverse cholesterol transport in apoE-/- mice. Plasma levels of high-density lipoprotein cholesterol (HDL-C), ABCA1 expression and atherosclerotic plaque collagen content were increased while plasma levels of low-density lipoprotein cholesterol (LDL-C) and atherosclerotic plaque sizes were reduced in Tan IIA-treated apoE-/- mice. These beneficial effects were, however, essentially blocked by knockdown of Omentin-1. CONCLUSION: Our results revealed that Tan IIA promotes cholesterol efflux and ameliorates lipid accumulation in macrophages most likely via the Omentin-1/ABCA1 pathway, reducing the development of aortic atherosclerosis.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Aterosclerose/tratamento farmacológico , Colesterol/metabolismo , Diterpenos de Abietano/farmacologia , Macrófagos/efeitos dos fármacos , Animais , Apolipoproteínas E/genética , Aterosclerose/metabolismo , Transporte Biológico , Linhagem Celular Tumoral , Diterpenos de Abietano/uso terapêutico , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Regulação para Cima
18.
Cell Biol Int ; 43(6): 623-633, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30958617

RESUMO

Traumatic brain injury (TBI) is one of the common diseases diagnosed in departments of neurosurgery. Apolipoprotein E (apoE) can improve the prognosis of TBI. In this study, we aimed to explore the effect of apoE in mechanically damaging neurons as well as its underlying molecular mechanism. Western blot analysis and immunofluorescence assay was performed to detect the expressions of associated proteins. The expressions of apoE, p38, and phosphorylation of P38 were increased in mechanically injured neurons compared with those of the non-injured ones. Neurons transfected into silencing apoE had no clear difference in the expression of apoE between injured and non-injured neurons. However, in the injured neurons, silencing apoE could significantly decrease apoE and p-P38 expressions. Oligodendrocytes were cultured in the medium collected from mechanically damaged si-apoE neurons. Furthermore, we found that mechanically injured si-apoE neurons could absorb the secreted apoE from the oligodendrocyte medium of the injured si-apoE-neuron, along with increasing of p-P38 expression at 24 h. The p38 MAPK inhibitor BIRB 796 almost did not affect the apoE expression at 24 h, but significantly reduced the p-P38 level at 24 and 72 h in injured si-apoE neurons cultured with oligodendrocyte medium of the injured si-apoE-neurons. Moreover, our result showed that neuronal repair effects in normal neurobasal medium (lowest levels of apoE and p-P38) and BIRB 796 medium (low level of p-P38) were more slow than those in the oligodendrocyte medium of the injured si-apoE-neurons. To conclude, our data demonstrated that mechanical injury of neurons stimulated oligodendrocytes to secrete apoE. The injured neurons could absorb secreted apoE. The expression of apoE contributed to the activation of p38 MAPK, which facilitated neuron repair.


Assuntos
Apolipoproteínas E/metabolismo , Lesões Encefálicas Traumáticas/patologia , Neurônios/metabolismo , Animais , Apolipoproteínas E/genética , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/metabolismo , Expressão Gênica , Naftalenos/farmacologia , Neurônios/patologia , Fosforilação , Pirazóis/farmacologia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
Zhonghua Yi Xue Za Zhi ; 99(15): 1156-1161, 2019 Apr 16.
Artigo em Chinês | MEDLINE | ID: mdl-31006219

RESUMO

Objective: To explore the relationship between apolipoprotein E (ApoE) gene polymorphism and hydrogen proton magnetic resonance spectroscopy ((1)H-MRS) in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment(aMCI). Methods: The cognitive function of 35 AD patients (AD group), 35 aMCI patients (aMCI group) and 36 normal controls (NC group) were evaluated by neuropsychological scales, including Mini-mental State Examination (MMSE) and Cambridge Cognitive Examination-Chinese version (CAMCOG-C). The genotypes of ApoE were analyzed by high-resolution melting assay. Brain regional metabolites were measured via (1)H-MRS technique with the regions of interest (ROIs) located in the left frontal lobe and left hippocampus. Results: The CAMCOG-C (NC group 94.00 (8.50);aMCI group 86.00(8.00);AD group 61.00(18.0)) and MMSE (NC group 29.00 (2.00);aMCI group 26.00(2.00);AD group 13.00(9.5)) scores in AD and aMCI group were significantly lower in comparison with that in NC group (P<0.05). There was multi-domain cognitive impairment both in AD and aMCI. The CAMCOG-C (ε4 carriers 76.00(28.00);no-ε4 carriers 89.00 (17.00)) and MMSE (ε4 carriers 23.00(16.00);no-ε4 carriers (27.00 (6.00))scores in ε4 carriers were significantly lower than those in no-ε4 carriers (P<0.05). The AD and aMCI groups showed decreased NAA/Cr ratio in the left hippocampus as well as elevated Cho/Cr ratio and MI/Cr in the left frontal lobe compared to the NC group (P<0.05). This change was even more pronounced in AD group when compared to aMCI group. The NAA/Cr ratio and Cho/Cr ratio in the left hippocampus in ε4 carriers were lower, the MI/Cr ratio in left frontal lobe in ε4 carriers was higher (P<0.05). Conclusions: ApoE gene polymorphism affects the alteration of (1)H-MRS in AD and aMCI patients. The combination of ApoE gene polymorphism and (1)H-MRS may be more useful to differentiate and diagnose AD and aMCI early.


Assuntos
Doença de Alzheimer , Apolipoproteínas E/genética , Disfunção Cognitiva , Doença de Alzheimer/genética , Disfunção Cognitiva/genética , Genótipo , Humanos , Espectroscopia de Ressonância Magnética , Testes Neuropsicológicos
20.
Neurobiol Aging ; 78: 178-185, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30947113

RESUMO

We investigated the effect of baseline Aß, sex, and APOE on longitudinal tau accumulation in cerebrospinal fluid (CSF) in clinically normal older adults. Two hundred thirty-nine participants (aged 56-89 years, clinical dementia rating = 0) underwent serial CSF collection for Aß1-42, total-tau (t-tau) and phospho-tau181P (p-tau). We used preprocessed data from fully automated Roche Elecsys immunoassays. A series of linear regressions were used to examine cross-sectional effects of Aß1-42, sex, and APOEε4 on baseline CSF tau and linear mixed models for longitudinal changes in CSF tau. Cross-sectionally, CSF t-tau and p-tau were associated with abnormal Aß1-42 and APOEε4 but not with sex. Longitudinally, low baseline CSF Aß1-42 levels, but not APOEε4 or sex, predicted faster p-tau accumulation. The relationship between baseline CSF Aß1-42 and tau accumulation was strongest in APOEε4 carriers, and particularly female carriers, relative to other groups. The current findings support an association between baseline CSF Aß1-42 and changes in CSF tau. Elevated risk in females, apparent only in carriers, reinforces findings of sex-related vulnerability in those with genetic predisposition for Alzheimer's disease.


Assuntos
Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteínas E/genética , Envelhecimento Saudável/líquido cefalorraquidiano , Heterozigoto , Fragmentos de Peptídeos/líquido cefalorraquidiano , Caracteres Sexuais , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Estudos Transversais , Feminino , Predisposição Genética para Doença/genética , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Risco
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