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1.
Neuron ; 109(15): 2363-2365, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34352209

RESUMO

In this issue of Neuron, Shi et al. (2021) show a protective role for the low-density lipoprotein receptor (LDLR) in tau pathology. Brain overexpression of LDLR lowers apolipoprotein E (apoE), suppresses microglial activation, preserves myelin, and ameliorates neurodegeneration, pointing the way toward potential new therapies.


Assuntos
Doença de Alzheimer , Tauopatias , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Encéfalo/metabolismo , Humanos , Lipoproteínas LDL , Receptores de LDL/genética , Receptores de LDL/metabolismo , Tauopatias/genética
2.
J Agric Food Chem ; 69(35): 10114-10120, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34428895

RESUMO

Our previous study showed that lycopene reduced the absorption of cholesterol in Caco-2 cells through inhibiting Niemann-Pick C1-Like 1 (NPC1L1) expression. Herein, we aimed to explore whether lycopene supplementation can decrease cholesterol absorption in the intestine and prevent atherosclerosis progression in high-fat diet (HFD)-fed apolipoprotein E knockout (ApoE-/-) mice. Male ApoE-/- mice were fed a high-fat diet with or without lycopene for 19 weeks. Supplementation of lycopene markedly lowered serum total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels. Additionally, serum high-density lipoprotein cholesterol (HDL-C) levels were increased after lycopene administration. Lycopene also downregulated the expression of NPC1L1 and hepatocyte nuclear factor-1α (HNF-1α) in the small intestine. Furthermore, the Oil Red O staining of the aorta and aortic sinus showed that lycopene supplementation remarkably reduced atherosclerotic lesions. These results indicated that lycopene inhibited intestinal cholesterol absorption and protected against HFD-induced atherosclerosis through inhibiting HNF-1α and NPC1L1 expression. Lycopene exhibits a potential antiatherosclerotic effect through suppressing intestinal cholesterol absorption.


Assuntos
Apolipoproteínas E , Aterosclerose , Animais , Apolipoproteínas E/genética , Aterosclerose/genética , Aterosclerose/prevenção & controle , Células CACO-2 , Colesterol , Fator 1-alfa Nuclear de Hepatócito , Humanos , Absorção Intestinal , Licopeno , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
3.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361033

RESUMO

Apolipoprotein E (ApoE), an essential plasma apolipoprotein, has three isoforms (E2, E3, and E4) in humans. E2 is associated with type III hyperlipoproteinemia. E4 is the major susceptibility gene to Alzheimer's disease (AD) and coronary heart disease (CHD). We investigated lipid metabolism and atherosclerotic lesions of novel humanized ApoE knockin (hApoE KI) rats in comparison to wide-type (WT) and ApoE knockout (ApoE KO) rats. The hApoE2 rats showed the lowest bodyweight and white fat mass. hApoE2 rats developed higher serum total cholesterol (TC), total triglyceride (TG), and low- and very low density lipoprotein (LDL-C&VLDL-C). ApoE KO rats also exhibited elevated TC and LDL-C&VLDL-C. Only mild atherosclerotic lesions were detected in hApoE2 and ApoE KO aortic roots. Half of the hApoE2 rats developed hepatic nodular cirrhosis. A short period of the Paigen diet (PD) treatment led to the premature death of the hApoE2 and ApoE KO rats. Severe vascular wall thickening of the coronary and pulmonary arteries was observed in 4-month PD-treated hApoE4 rats. In conclusion, hApoE2 rats develop spontaneous hyperlipidemia and might be suitable for studies of lipid metabolism-related diseases. With the PD challenge, hApoE4 KI rats could be a novel model for the analysis of vascular remodeling.


Assuntos
Apolipoproteínas E/genética , Aterosclerose/genética , Hiperlipidemias/genética , Metabolismo dos Lipídeos , Cirrose Hepática/genética , Animais , Apolipoproteínas E/metabolismo , Colesterol/sangue , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Técnicas de Introdução de Genes , Humanos , Lipoproteínas LDL/sangue , Masculino , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Ratos , Ratos Sprague-Dawley , Triglicerídeos/sangue , Remodelação Vascular
4.
Alzheimers Res Ther ; 13(1): 140, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404470

RESUMO

BACKGROUND: Alzheimer's disease, among other neurodegenerative disorders, spans decades in individuals' life and exhibits complex progression, symptoms and pathophysiology. Early diagnosis is essential for disease prevention and therapeutic intervention. Genetics may help identify individuals at high risk. As thousands of genetic variants may contribute to the genetic risk of Alzheimer's disease, the polygenic risk score (PRS) approach has been shown to be useful for disease risk prediction. The APOE-ε4 allele is a known common variant associated with high risk to AD, but also associated with earlier onset. Rare variants usually have higher effect sizes than common ones; their impact may not be well captured by the PRS. Instead of standardised PRS, we propose to calculate the disease probability as a measure of disease risk that allows comparison between individuals. METHODS: We estimate AD risk as a probability based on PRS and separately accounting for APOE, AD rare variants and the disease prevalence in age groups. The mathematical framework makes use of genetic variants effect sizes from summary statistics and AD disease prevalence in age groups. RESULTS: The AD probability varies with respect to age, APOE status and presence of rare variants. In age group 65+, the probability of AD grows from 0.03 to 0.18 (without APOE) and 0.07 to 0.7 (APOE e4e4 carriers) as PRS increases. In 85+, these values are 0.08-0.6 and 0.3-0.85. Presence of rare mutations, e.g. in TREM2, may increase the probability (in 65+) from 0.02 at the negative tail of the PRS to 0.3. CONCLUSIONS: Our approach accounts for the varying disease prevalence in different genotype and age groups when modelling the APOE and rare genetic variants risk in addition to PRS. This approach has potential for use in a clinical setting and can easily be updated for novel rare variants and for other populations or confounding factors when appropriate genome-wide association data become available.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Glicoproteínas de Membrana , Receptores Imunológicos , Fatores de Risco
5.
Mol Biol (Mosk) ; 55(4): 697-704, 2021.
Artigo em Russo | MEDLINE | ID: mdl-34432787

RESUMO

Adiponectin is an adipose tissue hormone affecting energy and lipoprotein metabolism and modulating inflammatory responses. However, the role of this adipokine in atherogenesis remains poorly understood. The aim of this study was to investigate the effect of adiponectin on the production of apolipoproteins (apo) A-l and E by human macrophages (MP). The study was conducted on macrophage-like cells of the THP-1 cell line of two differentiation terms, 3 and 5 days (3d and 5d). Adiponectin (10 µg/mL) stimulated the expression of apoA-1 gene at the mRNA level in 5d MP, but not in 3d MP. The level of apoE mRNA in MP under the action of adiponectin was not affected. Adiponectin suppressed macrophage TNF gene expression, while it induced the expression of IL-10 gene in 5d MP. The secreted levels of apoA-1 and apoE proteins under the action of adiponectin in macrophages of both periods of differentiation remained unchanged, while the level of the surface apoA-1 protein in 5d MP was decreasing. Incubation of 5d MP with the PPARα nuclear receptor antagonist MK-886 or with the nuclear receptor LXR agonist TO-901317 resulted in cancellation of the stimulating effect of adiponectin on apoA-1 gene expression. These data indicate that adiponectin, in addition to its anti-inflammatory action, has a modulating effect on production of apoA-1 by macrophages. The latter is probably one of the mechanisms of the influence of this adipokine on atherogenesis.


Assuntos
Adiponectina , Apolipoproteína A-I , Apolipoproteínas E , Aterosclerose , Adiponectina/genética , Apolipoproteína A-I/genética , Apolipoproteínas E/genética , Apolipoproteínas L , Humanos , Macrófagos
6.
Int J Mol Sci ; 22(13)2021 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-34281251

RESUMO

Apolipoprotein E (ApoE), a 34-kDa glycoprotein, as part of the high-density lipoprotein (HDL), has antioxidant, anti-inflammatory and antiatherogenic properties. The variability of ApoE expression in the course of some female fertility disorders (endometriosis, POCS), and other gynecological pathologies such as breast cancer, choriocarcinoma, endometrial adenocarcinoma/hyperplasia and ovarian cancer confirm the multidirectional biological function of ApoE, but the mechanisms of its action are not fully understood. It is also worth taking a closer look at the associations between ApoE expression, the type of its genotype and male fertility disorders. Another important issue is the variability of ApoE glycosylation. It is documented that the profile and degree of ApoE glycosylation varies depending on where it occurs, the type of body fluid and the place of its synthesis in the human body. Alterations in ApoE glycosylation have been observed in the course of diseases such as preeclampsia or breast cancer, but little is known about the characteristics of ApoE glycans analyzed in human seminal and blood serum/plasma in the context of male reproductive health. A deeper analysis of ApoE glycosylation in the context of female and male fertility will both enable us to broaden our knowledge of the biochemical and cellular mechanisms in which glycans participate, having a direct or indirect relationship with the fertilization process, and also give us a chance of contributing to the enrichment of the diagnostic panel in infertile women and men, which is particularly important in procedures involved in assisted reproductive techniques. Moreover, understanding the mechanisms of glycoprotein glycosylation related to the course of various diseases and conditions, including infertility, and the interactions between glycans and their specific ligands may provide us with an opportunity to interfere with their course and thus develop new therapeutic strategies. This brief overview details some of the recent advances, mainly from the last decade, in understanding the associations between ApoE expression and some female and male fertility problems, as well as selected female gynecological diseases and male reproductive tract disorders. We were also interested in how ApoE glycosylation changes influence biological processes in the human body, with special attention to human fertility.


Assuntos
Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Saúde Reprodutiva , Apolipoproteínas E/química , Feminino , Fertilidade/genética , Fertilidade/fisiologia , Expressão Gênica , Doenças dos Genitais Femininos/genética , Doenças dos Genitais Femininos/metabolismo , Doenças dos Genitais Masculinos/genética , Doenças dos Genitais Masculinos/metabolismo , Glicosilação , Humanos , Infertilidade Feminina/genética , Infertilidade Feminina/metabolismo , Infertilidade Masculina/genética , Infertilidade Masculina/metabolismo , Masculino , Polimorfismo Genético , Gravidez
7.
Sci Transl Med ; 13(603)2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34290056

RESUMO

Abdominal aortic aneurysm (AAA) is a potentially fatal vascular disease, but the underlying mechanisms remain unknown. Here, we tested the hypothesis that erythropoietin (EPO) may promote the formation of AAA. We found that EPO dose-dependently promoted the formation of AAA in both Apoe -/- (66.7%) and wild-type (WT) (60%) mice receiving a high dose of EPO. EPO monoclonal antibodies given to Apoe -/- mice receiving angiotensin II (AngII) stimulation resulted in a markedly lower incidence of AAA (from 86.7 to 20%, P < 0.001), and EPO receptor (EPOR) knockdown in Epor +/- Apoe -/- mice substantially reduced the incidence of AAA compared to Apoe -/- mice after AngII stimulation (from 86.7 to 45.5%, P < 0.05), further supporting the finding that EPO is a contributor to AAA formation. EPO-induced AAA resulted in increased microvessels, phagocyte infiltration, and matrix metalloproteinase secretion, as well as reduced collagen and smooth muscle cells (SMCs). Experiments in vitro and ex vivo demonstrated that EPO induced proliferation, migration, and tube formation of endothelial cells via the JAK2/STAT5 signaling pathway. In humans, serum EPO concentrations were higher in patients with AAA than in healthy individuals and correlated with the size of the AAA, suggesting a potential link between EPO and the severity of AAA in humans. In conclusion, we found that EPO promotes the formation of AAA in both Apoe -/- and WT mice by enhancing angiogenesis, inflammation, collagen degradation, and apoptosis of SMCs and that EPO/EPOR signaling is essential for AngII-induced AAA. The association between EPO and AAA in humans warrants further study.


Assuntos
Aneurisma da Aorta Abdominal , Eritropoetina , Angiotensina II , Animais , Aorta Abdominal , Apolipoproteínas E/genética , Modelos Animais de Doenças , Células Endoteliais , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
8.
Artigo em Inglês | MEDLINE | ID: mdl-34299687

RESUMO

Physical activity (PA) reduces the risk of cognitive decline (CD) in the general population. However, little is known about whether the presence of the apolipoprotein E epsilon 4 allele (APOE e4) could modify this beneficial effect. The aim of this systematic review was to analyze and synthetize the scientific evidence related to PA levels and CD risk in cognitively healthy APOE e4 carriers. Four electronic databases were analyzed. Only original articles with longitudinal study design were selected to analyze the relationship between PA and CD in APOE e4 carriers. Five studies were included in the systematic review. All studies except one stated that PA is a protective factor against CD in APOE e4 carriers. Moreover, partial support was found for the hypothesis that a greater amount and intensity of PA are more beneficial in CD prevention. The results support the idea that PA is a protective factor against CD in APOE e4 carriers. Nevertheless, it would be necessary to carry out further studies that would allow these findings to be contrasted.


Assuntos
Apolipoproteína E4 , Disfunção Cognitiva , Alelos , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Disfunção Cognitiva/genética , Disfunção Cognitiva/prevenção & controle , Exercício Físico , Genótipo , Humanos , Estudos Longitudinais
9.
Alzheimers Res Ther ; 13(1): 121, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210365

RESUMO

BACKGROUND: Arterial stiffening has emerged as an important risk factor for Alzheimer's disease (AD) and related dementias. Carotid-femoral pulse wave velocity has been proposed as a non-invasive and reproducible method to assess arterial stiffness. However, the association of pulse wave velocity with performance across multiple cognitive domains as well as interactions with in vivo AD biomarkers and apolipoprotein E (APOE) genotype has received limited study. METHOD: We studied 193 older adult volunteers (167 with normal cognition and 26 with mild cognitive impairment) who underwent comprehensive medical and neuropsychological evaluation at the University of California, San Diego Alzheimer's Disease Research Center. Cerebrospinal fluid (CSF) biomarkers were available on 123 participants (63%). Linear models examined whether pulse wave velocity significantly interacted with APOE ε4 status and CSF AD biomarker positivity (based on the ratio of total tau over beta-amyloid [tau/Aß42]) on memory, language, executive functioning, attention, and visuospatial abilities. RESULTS: After adjusting for demographic characteristics and vascular risk burden, across the entire sample, pulse wave velocity was associated with poorer executive functioning but not the performance in the other cognitive domains. When the modifying effects of AD genetic risk and CSF AD biomarkers were considered, pulse wave velocity interacted with APOE genotype and CSF tau/Aß ratio such that a stronger association between elevated pulse wave velocity and poorer memory performance was found among those positive for CSF and genetic AD markers. There were no significant interaction effects for non-memory cognitive domains. CONCLUSION: The findings suggest that pulse wave velocity, a non-invasive method to assess arterial wall properties, may be a useful marker of risk for cognitive decline, particularly among individuals who are APOE ε4 carriers or CSF AD biomarke0r-positive.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Idoso , Doença de Alzheimer/genética , Peptídeos beta-Amiloides , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Biomarcadores , Disfunção Cognitiva/genética , Genótipo , Humanos , Fragmentos de Peptídeos , Análise de Onda de Pulso , Proteínas tau
10.
Transl Psychiatry ; 11(1): 406, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34301914

RESUMO

Here we report how four major forms of Alzheimer's disease (AD) genetic risk-APOE-ε4, APOE-ε2, polygenic risk and familial risk-are associated with 273 traits in ~500,000 individuals in the UK Biobank. The traits cover blood biochemistry and cell traits, metabolic and general health, psychosocial health, and cognitive function. The difference in the profile of traits associated with the different forms of AD risk is striking and may contribute to heterogenous presentation of the disease. However, we also identify traits significantly associated with multiple forms of AD genetic risk, as well as traits showing significant changes across ages in those at high risk of AD, which may point to their potential roles in AD etiology. Finally, we highlight how survivor effects, in particular those relating to shared risks of cardiovascular disease and AD, can generate associations that may mislead interpretation in epidemiological AD studies. The UK Biobank provides a unique opportunity to powerfully compare the effects of different forms of AD genetic risk on the phenome in the same cohort.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Genótipo , Humanos , Herança Multifatorial , Fenótipo , Fatores de Risco
11.
Nat Commun ; 12(1): 4506, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34301930

RESUMO

Polygenic Risk Scores (PRS) for AD offer unique possibilities for reliable identification of individuals at high and low risk of AD. However, there is little agreement in the field as to what approach should be used for genetic risk score calculations, how to model the effect of APOE, what the optimal p-value threshold (pT) for SNP selection is and how to compare scores between studies and methods. We show that the best prediction accuracy is achieved with a model with two predictors (APOE and PRS excluding APOE region) with pT<0.1 for SNP selection. Prediction accuracy in a sample across different PRS approaches is similar, but individuals' scores and their associated ranking differ. We show that standardising PRS against the population mean, as opposed to the sample mean, makes the individuals' scores comparable between studies. Our work highlights the best strategies for polygenic profiling when assessing individuals for AD risk.


Assuntos
Doença de Alzheimer/genética , Apolipoproteínas E/genética , Estudo de Associação Genômica Ampla/métodos , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único , Alelos , Doença de Alzheimer/diagnóstico , Estudos de Casos e Controles , Frequência do Gene , Genética Populacional/métodos , Genética Populacional/estatística & dados numéricos , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Genótipo , Humanos , Reprodutibilidade dos Testes , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Fatores de Risco , Sensibilidade e Especificidade
12.
Lancet Neurol ; 20(8): 615-626, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34302786

RESUMO

BACKGROUND: Due to trisomy of chromosome 21 and the resultant extra copy of the amyloid precursor protein gene, nearly all adults with Down syndrome develop Alzheimer's disease pathology by the age of 40 years and are at high risk for dementia given their increased life expectancy compared with adults with Down syndrome in the past. We aimed to compare CSF biomarker patterns in Down syndrome with those of carriers of autosomal dominant Alzheimer's disease mutations to enhance our understanding of disease mechanisms in these two genetic groups at high risk for Alzheimer's disease. METHODS: We did a cross-sectional study using data from adults enrolled in the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study, a multisite longitudinal study of Alzheimer's disease in Down syndrome, as well as a cohort of carriers of autosomal dominant Alzheimer's disease mutations and non-carrier sibling controls enrolled in the Dominantly Inherited Alzheimer Network (DIAN) study. For ABC-DS, participants with baseline CSF, available clinical diagnosis, and apolipoprotein E genotype as of Jan 31, 2019, were included in the analysis. DIAN participants with baseline CSF, available clinical diagnosis, and apolipoprotein E genotype as of June 30, 2018, were evaluated as comparator groups. CSF samples obtained from adults with Down syndrome, similarly aged carriers of autosomal dominant Alzheimer's disease mutations, and non-carrier siblings (aged 30-61 years) were analysed for markers of amyloid ß (Aß1-40, Aß1-42); tau phosphorylated at threonine 181-related processes; neuronal, axonal, or synaptic injury (total tau, visinin-like protein 1, neurofilament light chain [NfL], synaptosomal-associated protein 25); and astrogliosis and neuroinflammation (chitinase-3-like protein 1 [YKL-40]) via immunoassay. Biomarker concentrations were compared as a function of dementia status (asymptomatic or symptomatic), and linear regression was used to evaluate and compare the relationship between biomarker concentrations and age among groups. FINDINGS: We assessed CSF samples from 341 individuals (178 [52%] women, 163 [48%] men, aged 30-61 years). Participants were adults with Down syndrome (n=41), similarly aged carriers of autosomal dominant Alzheimer's disease mutations (n=192), and non-carrier siblings (n=108). Individuals with Down syndrome had patterns of Alzheimer's disease-related CSF biomarkers remarkably similar to carriers of autosomal dominant Alzheimer's disease mutations, including reductions (all p<0·0080) in Aß1-42 to Aß1-40 ratio and increases in markers of phosphorylated tau-related processes; neuronal, axonal, and synaptic injury (p<0·080); and astrogliosis and neuroinflammation, with greater degrees of abnormality in individuals with dementia. Differences included overall higher concentrations of Aß and YKL-40 (both p<0·0008) in Down syndrome and potential elevations in CSF tau (p<0·010) and NfL (p<0·0001) in the asymptomatic stage (ie, no dementia symptoms). FUNDING: National Institute on Aging, Eunice Kennedy Shriver National Institute of Child Health and Human Development, German Center for Neurodegenerative Diseases, and Japan Agency for Medical Research and Development.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Síndrome de Down/líquido cefalorraquidiano , Adulto , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteínas E/genética , Biomarcadores/líquido cefalorraquidiano , Estudos Transversais , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Encefalite/líquido cefalorraquidiano , Feminino , Genótipo , Gliose/líquido cefalorraquidiano , Heterozigoto , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano
13.
Alzheimers Res Ther ; 13(1): 120, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193248

RESUMO

BACKGROUND: Associations of Apolipoprotein (APOE) ε2 or ε4 (APOE2 or APOE4) dosages with cognitive change may differ across racial groups. METHODS: Longitudinal data on 1770 middle-aged White and African American adults was compiled from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS 2004-2013) study. APOE2 and APOE4 dosages were the two main exposures, while v1 and annual rate of change in cognitive performance (between v1 and v2) on 11 test scores were the main outcomes of interest (v1: 2004-2009 and v2: 2009-2013). Mixed-effects linear regression models were conducted adjusting for socio-demographic, lifestyle, and health-related potential confounders. Race (African American vs. White) and sex within racial groups were main effect modifiers. RESULTS: Upon adjustment for multiple testing and potential confounders, APOE4 allelic dosage was associated with faster decline on a test of verbal memory among Whites only (CVLT-List A: γ12 = - 0.363 ± 0.137, p = 0.008), but not among African Americans. In contrast, among African American women, APOE4 dosage was linked to slower decline on a test of attention (BTA: γ12 = + 0.106 ± 0.035, p = 0.002), while no association was detected among African American men. APOE2 and APOE4 dosages showed inconsistent results in other domains of cognition overall and across racial groups that did not survive correction for multiple testing. CONCLUSIONS: In conclusion, APOE4 dosage was associated with faster decline on a test of verbal memory among Whites only, while exhibiting a potential protective effect among African American women in the domain of attention. Further longitudinal studies are needed to replicate our race and sex-specific findings.


Assuntos
Apolipoproteínas E , Disfunção Cognitiva , Adulto , Afro-Americanos , Apolipoproteínas E/genética , Cognição , Disfunção Cognitiva/etnologia , Disfunção Cognitiva/genética , Grupo com Ancestrais do Continente Europeu , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais
14.
Nutrients ; 13(7)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203181

RESUMO

BACKGROUND: Observationally plasma apolipoprotein E (apoE) is positively associated with ischemic heart disease (IHD). A Mendelian randomization (MR) study suggesting apoE is unrelated to cardiovascular mortality did not consider specific isoforms. We used MR to obtain estimates of plasma apoE2, apoE3 and apoE4 on IHD, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglycerides and apolipoprotein B (apoB). METHODS: We obtained independent genetic instruments from proteome genome-wide association studies (GWAS) and applied them to large outcome GWAS. We used univariable MR to assess the role of each isoform and multivariable MR to assess direct effects. RESULTS: In univariable MR, apoE4 was positively associated with IHD (odds ratio (OR) 1.05, 95% confidence interval (CI) 1.01 to 1.09), but apoE2 and apoE3 were less clearly associated. Using multivariable MR an association of apoE2 with IHD (OR 1.16, 95% CI 0.98 to 1.38) could not be excluded, and associations of apoE3 and apoE4 with IHD were not obvious. In univariable MR, apoE2 and apoE4 were positively associated with apoB, and a positive association of apoE2 with LDL cholesterol could not be excluded. Using multivariable MR apoE2 was positively associated with LDL cholesterol, and associations with apoB could not be excluded. After adjusting for apoB, no direct effects of apoE isoforms on IHD were evident. CONCLUSIONS: Plasma apoE2 and apoE4 may play a role in lipid modulation and IHD. Whether apoE could be a potential therapeutic target requires further clarification when larger genetic studies of apoE isoforms are available.


Assuntos
Apolipoproteínas E/sangue , Isquemia Miocárdica/sangue , Adulto , Apolipoproteína E2/sangue , Apolipoproteína E2/genética , Apolipoproteína E3/sangue , Apolipoproteína E3/genética , Apolipoproteína E4/sangue , Apolipoproteína E4/genética , Apolipoproteínas B/sangue , Apolipoproteínas B/genética , Apolipoproteínas E/genética , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lipídeos/sangue , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Isoformas de Proteínas , Triglicerídeos
15.
Int J Mol Sci ; 22(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34298986

RESUMO

Alzheimer's disease (AD) is the leading cause of dementia and cognitive function impairment. The multi-faced character of AD requires new drug solutions based on substances that incorporate a wide range of activities. Antioxidants, AChE/BChE inhibitors, BACE1, or anti-amyloid platelet aggregation substances are most desirable because they improve cognition with minimal side effects. Plant secondary metabolites, used in traditional medicine and pharmacy, are promising. Among these are the monoterpenes-low-molecular compounds with anti-inflammatory, antioxidant, enzyme inhibitory, analgesic, sedative, as well as other biological properties. The presented review focuses on the pathophysiology of AD and a selected group of anti-neurodegenerative monoterpenes and monoterpenoids for which possible mechanisms of action have been explained. The main body of the article focuses on monoterpenes that have shown improved memory and learning, anxiolytic and sleep-regulating effects as determined by in vitro and in silico tests-followed by validation in in vivo models.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Monoterpenos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Nootrópicos/uso terapêutico , Fitoterapia , Acetilcolina/fisiologia , Acetilcolinesterase/química , Doença de Alzheimer/metabolismo , Animais , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Apolipoproteínas E/genética , Apolipoproteínas E/fisiologia , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Encefalite/complicações , Encefalite/metabolismo , Humanos , Iridoides/uso terapêutico , Aprendizagem/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Modelos Moleculares , Monoterpenos/farmacologia , Proteínas do Tecido Nervoso/fisiologia , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Conformação Proteica , Ratos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Distúrbios do Início e da Manutenção do Sono/etiologia
16.
Aging (Albany NY) ; 13(13): 17237-17252, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34214049

RESUMO

Genetic background has been considered one of the important contributors to the rate of cognitive decline among patients with Alzheimer's disease (AD). We conducted a 4-year longitudinal follow-up study, recruited 255 AD and 44 mild cognitive impairment (MCI) patients, and used a data-driven trajectory analysis to examine the influence of selected AD risk genes on the age for and the rate of cognitive decline in Han Chinese population. Genotyping of selected single-nucleotide polymorphisms in the APOE, ABCA7, SORL1, BIN1, GAB2, and CD33 genes was conducted, and a Bayesian hierarchical model was fitted to analyze the trajectories of cognitive decline among different genotypes. After adjusting for sex and education years, the APOE ε4 allele was associated with an earlier mean change of -2.39 years in the age at midpoint of cognitive decline, the G allele in ABCA7 rs3764650 was associated with an earlier mean change of -1.75 years, and the T allele in SORL1 rs3737529 was associated with a later mean change of 2.6 years. Additionally, the rate of cognitive decline was associated with the APOE ε4 allele and SORL1 rs3737529. In summary, APOE and SORL1 might be the most important genetic factors related to cognitive decline in Han Chinese population.


Assuntos
Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Grupo com Ancestrais do Continente Asiático/genética , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/genética , Idoso , Idoso de 80 Anos ou mais , Apolipoproteínas E/genética , Feminino , Seguimentos , Genótipo , Humanos , Proteínas Relacionadas a Receptor de LDL/genética , Estudos Longitudinais , Masculino , Proteínas de Membrana Transportadoras/genética , Testes de Estado Mental e Demência , Polimorfismo de Nucleotídeo Único , Taiwan/epidemiologia
17.
Ann Acad Med Singap ; 50(6): 474-480, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34195754

RESUMO

INTRODUCTION: The apolipoprotein E (APOE) gene is a promising candidate for the diagnosis of hyperlipoproteinaemia and atherosclerosis. Polymorphisms in APOE have been reported to result in differential efficacies of statin drugs in atherosclerotic cardiovascular disease. METHODS: We classified the APOE genotypes of 225 patients treated with atorvastatin, and analysed the relation between genotypes and serum lipid levels. RESULTS: The baseline serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were significantly lower in carriers of APOE ε3 than of APOE ε4 genotypes. The serum levels of TC and LDL-C decreased significantly after 1 month of atorvastatin treatment. Atorvastatin has a higher significant effect in reducing serum TC and LDL-C levels in patients with the APOE ε4 genotype. CONCLUSION: Polymorphism in the APOE gene is related to the efficacy of atorvastatin in reducing the serum levels of TC and LDL-C.


Assuntos
Apolipoproteínas E , Aterosclerose , Doenças Cardiovasculares , Inibidores de Hidroximetilglutaril-CoA Redutases , Apolipoproteínas E/genética , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Genótipo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipídeos
18.
Alzheimers Res Ther ; 13(1): 130, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34266503

RESUMO

BACKGROUND: Leukocyte telomere length (LTL) has been shown to predict Alzheimer's disease (AD), albeit inconsistently. Failing to account for the competing risks between AD, other dementia types, and mortality, can be an explanation for the inconsistent findings in previous time-to-event analyses. Furthermore, previous studies indicate that the association between LTL and AD is non-linear and may differ depending on apolipoprotein E (APOE) ε4 allele carriage, the strongest genetic AD predictor. METHODS: We analyzed whether baseline LTL in interaction with APOE ε4 predicts AD, by following 1306 initially non-demented subjects for 25 years. Gender- and age-residualized LTL (rLTL) was categorized into tertiles of short, medium, and long rLTLs. Two complementary time-to-event models that account for competing risks were used; the Fine-Gray model to estimate the association between the rLTL tertiles and the cumulative incidence of AD, and the cause-specific hazard model to assess whether the cause-specific risk of AD differed between the rLTL groups. Vascular dementia and death were considered competing risk events. Models were adjusted for baseline lifestyle-related risk factors, gender, age, and non-proportional hazards. RESULTS: After follow-up, 149 were diagnosed with AD, 96 were diagnosed with vascular dementia, 465 died without dementia, and 596 remained healthy. Baseline rLTL and other covariates were assessed on average 8 years before AD onset (range 1-24). APOE ε4-carriers had significantly increased incidence of AD, as well as increased cause-specific AD risk. A significant rLTL-APOE interaction indicated that short rLTL at baseline was significantly associated with an increased incidence of AD among non-APOE ε4-carriers (subdistribution hazard ratio = 3.24, CI 1.404-7.462, P = 0.005), as well as borderline associated with increased cause-specific risk of AD (cause-specific hazard ratio = 1.67, CI 0.947-2.964, P = 0.07). Among APOE ε4-carriers, short or long rLTLs were not significantly associated with AD incidence, nor with the cause-specific risk of AD. CONCLUSIONS: Our findings from two complementary competing risk time-to-event models indicate that short rLTL may be a valuable predictor of the AD incidence in non-APOE ε4-carriers, on average 8 years before AD onset. More generally, the findings highlight the importance of accounting for competing risks, as well as the APOE status of participants in AD biomarker research.


Assuntos
Doença de Alzheimer , Apolipoproteína E4 , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Genótipo , Humanos , Incidência , Leucócitos , Fatores de Risco , Telômero
19.
ACS Chem Neurosci ; 12(15): 2749-2764, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34275270

RESUMO

Alzheimer's disease (AD) is the most common neurodegenerative disorder with obscure pathogenesis and no disease-modifying therapy to date. AD is multifactorial disease that develops from the complex interplay of genetic factors and environmental exposures. The E4 allele of the gene encoding apolipoprotein E (APOE) is the most common genetic risk factor for AD, whereas the E2 allele acts in a protective manner. A growing amount of epidemiological evidence suggests that several lifestyle habits and environmental factors may interact with APOE alleles to synergistically affect the risk of AD development. Among them, physical exercise, dietary habits including fat intake and ketogenic diet, higher education, traumatic brain injury, cigarette smoking, coffee consumption, alcohol intake, and exposure to pesticides and sunlight have gained increasing attention. Although the current evidence is inconsistent, it seems that younger APOE4 carriers in preclinical stages may benefit mostly from preventive lifestyle interventions, whereas older APOE4 noncarriers with dementia may show the most pronounced effects. The large discrepancies between the epidemiological studies may be attributed to differences in the sample sizes, the demographic characteristics of the participants, including age and sex, the methodological design, and potential related exposures and comorbidities as possible cofounding factors. In this Review, we aim to discuss available evidence of the prominent APOE genotype-environment interactions in regard to cognitive decline with a focus on AD, providing an overview of the current landscape in this field and suggesting future directions.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Genótipo , Humanos , Estilo de Vida
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