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1
Reverté, Soler Ingrid. "Neurobehavioural effects associated with postnatal exposure to decabromodiphenyl ether in apoe2, apoe3 and apoe4 transgenic mice." Doctoral thesis, Universitat Rovira i Virgili, 2012. http://hdl.handle.net/10803/76782.
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El Decabromodifenil èter (BDE-209) és un retardant de la flama àmpliament utilitzat i font de preocupació a causa de la toxicitat mostrada per altres Difenil Èters Polibromats (PBDEs). La presència de PBDEs en la llet materna fa preocupant la seva exposició durant el desenvolupament. Pensem que l’exposició primerenca a BDE-209 pot produir efectes a llarg termini i interactuar amb factors genètics, com el genotip de l’ApolipoproteinaE. Ratolins portadors de les diferents isoformeshumanes de l’ApoE foren tractats amb una dosi oral aguda de 0, 10 o 30 mg / kg de BDE-209 en el dia postnatal 10 i van ser avaluats per neurocomportament durant el desenvolupament, a l'edat adulta i la vellesa. L’exposició a BDE-209 indueix un retard en el desenvolupament físic i neuromotor i en la compactació de la mielina en els ratolins ApoE2, disminueix els nivells de tiroxina lliure en les femelles adultes i disminueix l'activitat en ratolins ApoE4. Els efectes més consistents durant tota la vida s'observen en ratolins ApoE3 i consisteixen en problemes d'aprenentatge als 4 mesos, i problemes d'aprenentatge i memòria i un augment de l'ansietat als 12 mesos.Decabromodiphenyl Ether (BDE-209) is a flame retardant widely used and source of concern because ofthe toxicity showed by other Polibrominateddiphenyl ethers (PBDEs). The presenceof PBDEs in human’s breast milkmakes worrying its exposure during development. We hypothesised that an early exposure to BDE-209 can induce long-term impairments and interact with genetic factors, such as ApolipoproteinE genotype. Mice carrying the different Human ApoE isoforms treated with an acute oral dose of 0, 10 or 30 mg/kg of BDE-209 on postnatal day 10 were assessed for neurobehaviourduring development, in young adulthood and old age. BDE-209 exposure inducesadelay in physic and neuromotordevelopment and in myelin compaction in ApoE2 mice, decreases the levels of free thyroxin in adult femalesand decreases activity in ApoE4 mice. The most consistent effects across the lifespan are observed in ApoE3 mice and consist of impaired learning at 4 months, and impaired learning and memory and increased anxiety at 12 months.
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Donovan, Alexandra. "Comparative Biophysical Analysis of APOE3 and APOE4| A Mechanistic Investigation." Thesis, California State University, Long Beach, 2017. http://pqdtopen.proquest.com/#viewpdf?dispub=10606132.
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Apolipoprotein E is an exchangeable apolipoprotein whose isoforms are associated with various disease risk profiles. Individuals bearing the APOE ϵ4 allele are at increased risk for developing Alzheimer’s disease compared to those bearing the APOE ϵ3 allele. The two isoforms differ in amino acid at position 112: apoE3 bears a Cys while apoE4 bears an Arg. It is hypothesized that the Cys to Arg substitution in apoE4 causes a decrease in stability in comparison to apoE3, which is exaggerated at endosomal pH <6.0. In our study, changes in secondary structure were monitored using circular dichroism at pH 7.4 and pH 3.5. Chemical denaturation indicated that both apoE3 and apoE4 retained their helical secondary structure at the lower pH, with a biphasic and monophasic guanidine HCl denaturation profile, respectively. Tertiary structure was monitored at both pH’s through fluorescence spectral characteristics and mobility of a fluorescent probe attached to each of the 7 major amphipathic α-helices of apoE3 and apoE4. The data showed decreases in fluorescence emission (FE), changes in fluorescence polarization (FP), and fluctuations in probe mobility, which were interpreted as likely formation of a molten globule. Formation of a molten globule appeared to occur during denaturation primarily for apoE4, and thermodynamic parameters of apoE4 showed a lower stability than apoE3, with a larger effect of pH. Taken together, our results suggest that the acidic pH in the endosomal compartments could interact with the native structure of apoE4 to generate a molten globule state that is able to bind endosomal membranes, other proteins, or itself. This study offers mechanistic insight into the impact of the single residue difference between apoE3 and apoE4 with regard to folding/unfolding behavior, and with regard to its physiological and pathological implications.
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Cieslak, Stephen Gerard. "The Effects of L-Cysteine on Alzheimer's Disease Pathology in APOE2, APOE3, and APOE4 Homozygous Mice." BYU ScholarsArchive, 2016. https://scholarsarchive.byu.edu/etd/6585.
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The APOE gene is of profound importance regarding the onset of Alzheimer's disease (AD). From the small physical differences among the protein products of the isoforms of this gene arises a profound difference in their physiologies. For example, the APOE2 isoform confers resistance to AD, the APOE3 isoform confers neutral susceptibility to AD, and the APOE4 isoform confers proneness to AD. L-cysteine is an amino acid that has several anti-AD properties, among which are its ability to sequester iron and form glutathione – a powerful antioxidant – and therefore may be a promising potential dietary supplement for ameliorating AD pathology. In our experiment, we fed Mus musculus (mice) homozygous for APOE2, APOE3, and APOE4 either a control diet or a diet high in L-cysteine. Using Western blotting analysis, we quantified Amyloid β (Aβ), hyper-phosphorylated Tau (HP-Tau), and the three APOE proteins that we extracted from post-mortem brains of APOE2, APOE3, and APOE4 homozygous mice of 3-, 6-, 9-, and 12-month ages. We calculated a three-way ANOVA on a sample of 86 mice to examine the effect of age, genotype, and diet on protein quantities. We found that administration of L-cysteine trends towards lowering levels of Aβ in each cohort, but this effect is statistically insignificant. On the other hand, L-cysteine caused a significant decrease in APOE production with regard to diet [F(1,62) = 6.17, p=0.02], indicating that less APOE is produced due to the decrease in Aβ burden. Furthermore, administration of L-cysteine revealed no significant impact on or trends regarding HP-Tau deposition between diet types for each cohort. However, we observed that L-cysteine appeared to nullify the increasing trend in HP-Tau deposition between APOE2 and APOE4 cohorts. Thus, L-cysteine may be weakly affecting HP-Tau deposition via its ability to somewhat reduce Aβ burden and consequently prevent the shutdown of the proteosomes responsible for the degradation and clearance of HP-Tau. Taken together, these data suggest that L-cysteine should be considered as an intervention for AD pathology.
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Bour, Alexandra. "Implication d'un dérivé sécrété du précurseur de la protéine β-amyloi͏̈de (sAPP695) et de différentes isoformes de l'apolipoprotéine E humaine (apoE3 et apoE4 ) dans les processus mnésiques chez la Souris." Université Louis Pasteur (Strasbourg) (1971-2008), 2004. https://publication-theses.unistra.fr/public/theses_doctorat/2004/BOUR_Alexandra_2004.pdf.
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Une perturbation du métabolisme du précurseur de la protéine beta-amyloi͏̈de (APP) est associée à la maladie d'Alzheimer (MA) et à l'apparition de troubles mnésiques liés à l'âge. Cette perturbation semble affecter le niveau cérébral de son dérivé soluble, le sAPP, qui possède des propriétés promnésiantes. D'autre part, l'allèle epsilon 4, mais pas l'allèle epsilon 3, du gène de l'apolipoprotéine E (apoE) est un facteur de risque génétique de la MA et des troubles mnésiques liés à l'âge. En outre, l'apoE semble influencer le métabolisme de l'APP. Les effets d'une administration intracérébroventriculaire de sAPP exogène à des souris lors de tâches de reconnaissance d'objet ou spatiale et d'apprentissage opérant indiquent qu'il favorise les mécanismes très précoces de formation de la mémoire. De plus, le blocage des sAPP endogènes par des anticorps affecte les performances mnésiques, ce qui confirme leur rôle dans les processus de consolidation de la mémoire. Parallèlement à cette étude, nous avons mis en évidence une influence néfaste du système de ventilation des salles d'hébergement affectant les performances mnésiques des souris. Les performances de souris transgéniques apoE3 et apoE4 (respectivement porteuses homozygotes de l'allèle humain epsilon 3 et epsilon 4) " âgées " (14-15 mois), ont été évaluées dans des tâches de reconnaissance spatiale et de mémoire spatiale dans la piscine de Morris, ainsi que des tâches d'évitement actif et passif. Les souris apoE4 femelles, en particulier, présentent de faibles performances de mémoire et apparaissent donc comme un bon modèle d'étude des troubles mnésiques liés à l'âge. Enfin, l'administration de sAPP a permis de restaurer les performances de mémoire spatiale des souris apoE4 femelles " âgées " dans la piscine de Morris. L'ensemble de ces résultats suggère que la modulation des niveaux de sAPP cérébraux pourrait permettre de traiter les déficits cognitifs liés au vieillissement en général, et à la MA en particulierAn alteration of the beta-amyloid precursor protein (APP) metabolism is associated with Alzheimer's disease (AD) as well as age-related memory impairments. This alteration seems to affect cerebral level of sAPP, a promnestic and soluble form of APP. On the other hand, the epsilon 4 allele, but not the epsilon 3 allele, of apolipoprotéine E (apoE) gene is a genetic risk factor for AD and for age-related memory impairments. Moreover, APP metabolism seems to be influenced by apoE. First, the effects of exogenous sAPP administration in mice were evaluated in object recognition, spatial recognition and bar-press learning tasks. According to the results, sAPP seems to promote early memory processes. The post-training blockade of endogenous sAPPs with specific antibodies induced memory deficits suggesting a central role of sAPPs in memory consolidation mechanisms. Besides this study, we showed the deleterious effect of the new ventilation system of some animal housing rooms on mice memory performance. Then, the memory performance of "aged" (14-15 months) apoE3 and apoE4 transgenic mice (homozygous carriers of the human apoE allele epsilon 3 and epsilon 4, respectively) were evaluated in spatial memory tasks (spatial recognition and Morris water maze) and active and passive avoidance memory tasks. Compared to apoE3 mice, apoE4 mice, especially females, showed more severe memory deficits. Thus, apoE4 female mice appear as a good model for the study of age-related memory deficits. In a last experiment using the Morris water maze task, the administration of sAPP restored a good level of spatial memory performance in "aged" female apoE4 mice. Altogether, our results suggest that the modulation of cerebral sAPP levels must be considered as a potential therapeutic approach in the treatment of age-related memory deficits in general, or those associated with AD in peculiar
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Cambon, Karine. "Influence of ApoE polymorphism on synaptic morphometry during aging in the dentate gyrus of ApoE knockout and human ApoE transgenic mice." Thesis, [n.p.], 2000. http://oro.open.ac.uk/19118/.
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Pandeirada, Ana Raquel Gonçalves. "Association between common lipid metabolism genes polymorphisms and sporadic colorectal adenocarcinoma risk." Master's thesis, Universidade de Aveiro, 2015. http://hdl.handle.net/10773/16151.
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Mestrado em Biomedicina MolecularLipids can modulate the risk of developing sporadic colorectal adenocarcinoma (SCA), since alterations into lipid metabolism and transport pathways influence directly cholesterol and lipids absorption by colonic cells and indirectly reactive oxygen species (ROS) synthesis in rectum cells due to lipid accumulation. Lipid metabolism is regulated by several proteins APOA1, APOB, APOC3, APOE, CETP, NPY, PON1 and PPARG that could influence both metabolism and transport processes. Is been reported that several common single-nucleotide polymorphisms (SNPs) in these genes could influence their function and/or expression, changing lipid metabolism balance. Thus, genetic changes in those genes can influence SCA development, once the majority of them were never studied in this disease. Furthermore, there are contradictory results between some studied polymorphisms and SCA risk. Thus, the aim of this study was to explore and describe lipid metabolism-associated genes common polymorphisms (APOA1 -75 G>A; APOB R3500Q; APOC3 C3175G, APOC3 T3206G; APOE Cys112/158Arg; CETP G279A, CETP R451Q; NPY Leu7Pro; PON1 Q192R; PPARG Pro12Ala) status among SCA, and their relationship with SCA risk. Genotyping of common lipid metabolism genes polymorphisms (APOA1 75 G>A; APOB R3500Q; APOC3 C3175G, APOC3 T3206G; APOE Cys112/158Arg; CETP G279A, CETP R451Q; NPY Leu7Pro; PON1 Q192R; PPARG Pro12Ala) were done by PCR-SSP techniques, from formalin-fixed and paraffin-embedded biopsies of 100 healthy individuals and 68 SCA subjects. Mutant genotypes of APOA1 -75AA (32% vs 12%; p=0.001; OR=3.51; 95% CI 1.59-7.72); APOB 3500AA (7% vs 0%; p=0.01); APOC3 3175GG (19% vs 2%; p=0.0002; OR=11.58; 95% CI 2.52-53.22), APOC3 3206GG (19% vs 0%; p<0.0001); CETP 279AA (12% vs 1%; p=0.003; OR=13.20; 95% CI 1.61-108.17), CETP 451AA (16% vs 0%; p<0.0001); NPY 7CC (15% vs 0%; p<0.0001); PPARG 12GG (10% vs 0%; p=0.001); and heterozygote genotype PON1 192AG (56% vs 22%; p<0.0001; OR=4.49; 95% CI 2.298.80) were found associated with SCA prevalence. While, APOE E4/E4 (0% vs 8%; p=0.02) mutant haplotype seemed to have a protective effect on SCA. Moreover, it also been founded differences between APOB 3500GA, APOC3 3206TG, CETP 279AA genotypes and PPARG 12Ala allele prevalence and tissue localization (colon vs rectum). These findings suggest a positive association between most of common lipid metabolism genes polymorphisms studied and SCA prevalence. Dysregulation of APOA1, APOB, APOC3, CETP, NPY, PON1 and PPARG genes could be associated with lower cholesterol plasma levels and increase ROS among colon and rectum mucosa. Furthermore, these results also support the hypothesis that CRC is related with intestinal lipid absorption decrease and secondary bile acids production increase. Moreover, the polymorphisms studied may play an important role as biomarkers to SCA susceptibility.
Os lípidos podem modular o risco de desenvolver Adenocarcinoma Colorectal Esporádico (ACE), uma vez que alterações nas vias do metabolismo e do transporte lipídico podem influenciar diretamente a absorção do colesterol e dos lípidos pelas células do cólon e indiretamente a síntese de espécies reativas de oxigénio (ERO) no reto, devido à acumulação de lípidos. O metabolismo lipídico é regulado por várias proteínas (APOA1, APOB, APOC3, APOE, CETP, NPY, PON1, PPARG) que podem influenciar o metabolismo e o transporte de lípidos. Tem sido reportados nestes genes, vários polimorfismos comuns (SNP) que podem alterar a sua função e/ ou a expressão, causando um desequilíbrio no metabolismo dos lípidos. Estas alterações genéticas podem influenciar o desenvolvimento de ACE, no entanto a maioria dos polimorfismos nunca foram estudados nesta patologia. Além disso, existem resultados contraditórios entre alguns dos polimorfismos e o risco de ACE. Deste modo, o objetivo deste estudo foi explorar e descrever o efeito dos polimorfismos comuns de genes associados ao metabolismo lipídico (APOA1 -75 G>A; APOB R3500Q; APOC3 C3175G, APOC3 T3206G; APOE Cys112/158Arg; CETP G279A, CETP R451Q; NPY Leu7Pro; PON1 Q192R; PPARG Pro12Ala) no ACE e a sua relação com o risco de desenvolver ACE. A genotipagem dos polimorfismos comuns de genes associados ao metabolismo lipídico (APOA1 -75 G>A; APOB R3500Q; APOC3 C3175G, APOC3 T3206G; APOE Cys112/158Arg; CETP G279A, CETP R451Q; NPY Leu7Pro; PON1 Q192R; PPARG Pro12Ala) foi efetuada pela técnica de PCR-SSP, a partir de biópsias incluídas em parafina e fixadas em formol de 100 indivíduos saudáveis e de 68 indivíduos com ACE. Os genótipos mutantes APOA1 -75AA (32% vs 12%; p=0.001; OR=3.51; 95% CI 1.59-7.72); APOB 3500AA (7% vs 0%; p=0.01); APOC3 3175GG (19% vs 2%; p=0.0002; OR=11.58; 95% CI 2.52-53.22), APOC3 3206GG (19% vs 0%; p<0.0001); CETP 279AA (12% vs 1%; p=0.003; OR=13.20; 95% CI 1.61-108.17), CETP 451AA (16% vs 0%; p<0.0001); NPY 7CC (15% vs 0%; p<0.0001); PPARG 12GG (10% vs 0%; p=0.001); e o genótipo heterozigótico PON1 192AG (56% vs 22%; p<0.0001; OR=4.49; 95% CI 2.29-8.80) demonstraram estar associados à prevalência de ACE. Enquanto, o haplótipo mutante APOE E4/E4 (0% vs 8%; p=0.02) mostrou ter um efeito protetor no ACE. Adicionalmente, também foram encontradas diferenças entre a prevalência e a localização tumoral (cólon ou reto) para os genótipos APOB 3500GA, APOC3 3206TG, CETP 279AA e para o alelo PPARG 12Ala. Estes resultados sugerem uma associação positiva entre a maioria dos polimorfismos genéticos comuns estudados envolvidos no metabolismo lipídico e a prevalência de ACE. A desregulação dos genes APOA1, APOB, APOC3, CETP, NPY, PON1, PPARG poderá estar associada com a diminuição dos níveis plasmáticos de colesterol e o aumento de ERO na mucosa do colon e do reto. Para além disso, estes resultados também suportam a hipótese de que o CCR esta relacionado com a diminuição da absorção intestinal e com o aumento da produção de ácidos biliares secundários. Adicionalmente, os polimorfismos estudados podem desempenhar um importante papel como biomarcadores de suscetibilidade para ACE.
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Evans, Vanessa. "Intramuscular gene transfer of apolipoprotein E (ApoE) to reverse hyperlipidaemia and atherosclerosis in ApoE-deficient mice." Thesis, University College London (University of London), 2007. http://discovery.ucl.ac.uk/1444704/.
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Plasma ApoE has multiple atheroprotective actions, including clearance of cholesterol-rich remnant lipoproteins, and is an attractive gene therapy candidate to treat atherosclerosis. Here, I focus on the single intramuscular injection of an ApoE-expressing vector, non-viral DNA (plasmid) or adeno-associated virus (AAV), as a safe and effective treatment to alleviate hypercholesterolaemia and atherosclerosis in ApoE-deficient (ApoE" ") mice. Firstly, I constructed expression plasmids harbouring human ApoE3 cDNA, driven by two muscle-specific (CK6 and C512) and one ubiquitous (CAG) promoter. The CAG-driven plasmid was injected into tibialis anterior muscles, pre-treated with hyaluronidase, of young ApoE"'" mice and, provided the injection site was electropulsed, gave strong local expression of ApoE3 protein at 1 week (13.38 7.46jig ApoE3 per muscle). This amount was much greater than the CK6- and C512-driven plasmids (0.61 0.38 and 0.45 0.38/ig, respectively), but in all mice plasma ApoE3 levels were below the detection limit (<15ng/ml) and did not ameliorate the hyperlipidaemia. Next, I generated both single-stranded (ss) and self- complementary (sc) AAV2/7 vectors. At 1, 2 and 4 weeks, ApoE was readily measured in the plasma of ApoE'" mice injected with the ssAAV2/7.CAG vector, reaching levels of 1.4/ig/ml, whereas plasma ApoE was again undetected after administration of the CAG-driven plasmid . By contrast, both ssAAV2/7 and scAAV2/7 vectors driven by the muscle-specific promoters performed poorly and ApoE could not be detected in plasma. Therefore, for my final experiment I pseudotyped the ssAAV2.CAG.ApoE3 vector with the robust serotypes 8 and 9, and directly compared their efficiency with ssAAV2/7.CAG.ApoE3 in ApoE"" mice. After 1 week plasma ApoE had reached 2ug/ml in ssAAV2/7 and ssAAV2/8-treated animals, and persisted at l-2ug/ml throughout the 13 week study, whereas the ssAAV2/9 vector was less effective and gave only 0.5ug ApoE/ml. Disappointingly, however, these concentrations of plasma ApoE were still insufficient to have hypolipidaemic effects or to inhibit plaque development in the brachiocephalic artery. In conclusion, although electropulsation enhanced plasmid-mediated transgene expression from skeletal muscle, rAAV was a more efficient gene transfer vector and modest additional optimisation should provide therapeutic levels of ApoE3 in plasma.
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Rantsi, P. (Petra). "Apoe 4-alleelien rooli saamelaisväestön muistisairauksissa." University of Oulu, 2017. http://urn.fi/URN:NBN:fi:oulu-201711083079.
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Alzheimerin tauti (AT) on yleisin etenevä muistisairaus. Eteneviin muistisairauksiin luetaan myös aivoverenkiertosairauden muistisairaus, Lewyn kappale- patologiaan liittyvät aivoja rappeuttavat sairaudet ja otsa-ohimolohkorappeumat. Elimistön rasva- aineenvaihduntaan liittyvän apolipoproteiini E4- (ApoE4) alleelin on todettu olevan sydän- ja verisuonisairauksien, kuten myös AT:n myöhemmällä iällä alkavan muodon geneettinen riskitekijä. ApoE4-alleelin yhteyttä muihin eteneviin muistisairauksiin ei ole osoitettu.
Vaikka ApoE4:n roolia muistisairauksien ja etenkin AT:n riskitekijänä on tutkittu maailmalla runsaasti eri väestöissä, ApoE4-alleelin roolia saamelaisten muistisairauksissa ei ole aiemmin tutkittu. Yksittäisen aiemman tutkimuksen perusteella Suomen saamelaisista 5%:lla on E2-, 64%:lla E3- ja 31%:lla E4- alleeli. Tutkimuksen tavoitteena oli selvittää ApoE4- alleelin esiintyminen Suomen Lapin saamelaisväestön muistisairauspotilailla. Tutkimukseen osallistui yhteensä 50 saamelaista potilasta, joilla oli todettu muistihäiriö tai muistisairauden diagnoosi. Laskimoverinäytteet ApoE-fenotyypitystä varten ja kyselykaavakkeiden tiedot kerättiin saamea puhuvan sairaanhoitajan avulla.
ApoE4- alleeli esiintyi yhteensä 78%:lla potilaista (n=39). Apolipoproteiini E-fenotyyppiä E3/E3 kantoi 22% (n=11) potilaista, E3/E4 62% (n=31), E4/E4 14% (n=7) ja E2/E4 2 % (n=1) tutkittavista. Verrokkeja tutkimuksessa ei ollut, mutta tuloksia verrattiin aiempaan tietoon ApoE-alleelien esiintyvyyteen sekä saamelaisilla että maailmanlaajuisesti AT:a sairastavilla. Yhteenvetona voidaan todeta, että ApoE4 on tärkeä riskigeeni muistisairauksille myös saamelaisväestössä. Lisäksi huomionarvoista on, että ApoE4-alleelin esiintyminen saamelaisväestön muistipotilailla on korkein, mitä on kuvattu missään aiemmassa muistipotilaiden ja AT-tutkimuksissa.
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Carvalho, Liliana Patrícia Rodrigues de. "Genetic profiling of ApoE in dementia." Master's thesis, Universidade de Aveiro, 2012. http://hdl.handle.net/10773/10720.
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Mestrado em Biomedicina MolecularA demência é uma das principais causas de incapacidade entre os idosos, afetando mais de 36 milhões de pessoas em todo o mundo. É caracterizada pela deterioração progressiva das funções cognitivas, resultando em dificuldades no desempenho das atividades diárias do indivíduo. A idade de aparecimento dos sintomas, bem como a sua taxa de progressão, são variáveis entre a maior parte das demências, sendo estas geralmente caracterizadas por uma natureza progressiva, aumentando de gravidade ao longo do tempo. Entre os tipos mais frequentes de demência encontram-se a Doença de Alzheimer (DA), Demência Vascular, Demência de Corpos de Lewy e Demência Frontotemporal. O diagnóstico diferencial das demências é realizado tipicamente por testes neuro-psicológicos (para a exclusão de outras demências) e por exames imagiológicos. Contudo, muitos dos sintomas clínicos característicos podem sobrepor-se entre os diversos tipos de demência, o que pode constituir um problema devido a falta de especificidade e erros de diagnóstico. A compreensão dos fatores de risco ambientais e genéticos que podem modular o aparecimento e/ou progressão de doenças abre novas perspetivas relativamente à gestão destas neuropatologias. O gene da apolipoproteína E (ApoE) é reconhecido como o maior fator de risco na demência, desempenhando um papel central em particular no desenvolvimento da DA, sendo que os portadores do alelo ε4 são mais suscetíveis para a doença. Além disso, possíveis associações foram também propostas entre este gene e outras doenças neurológicas, sendo no entanto estes dados ainda controversos. Assim, o objetivo principal deste trabalho consistiu em determinar as frequências alélicas e genotípicas do gene ApoE num grupo de estudo piloto de pacientes com demência na região de Aveiro. Este grupo foi subdividido com base no diagnóstico neuroquímico, no qual foram avaliados os níveis de Aβ1-42, Tau-total e fosfo-Tau 181 no líquido cefalorraquidiano dos pacientes. Como resultado, observou-se que o alelo ε3 foi o mais frequente no grupo total, independentemente do tipo de patologia, e que o alelo ε2 foi o menos comum. O alelo ε4 foi de facto mais frequente em pacientes com DA do que em pacientes com outras neuropatologias, o que está de acordo com a relação proposta por outros autores. Adicionalmente, foi possível verificar que a frequência deste alelo nos pacientes com patologia amilóide é semelhante à observada no grupo DA, sugerindo um papel relevante para o ApoE no metabolismo e acumulação cerebral do Aβ. Consequentemente, estes indivíduos podem ter uma maior suscetibilidade para o desenvolvimento de DA no futuro. Deste modo, os nossos dados corroboram a ideia de que o alelo ε4 é um forte fator de risco para a DA e que deve ser considerado como um teste genético relevante que pode contribuir para o diagnóstico clínico da demência.
Dementia is one of the leading causes of disability among the elderly, affecting over 36 million people worldwide. It is characterized by progressive deterioration in cognitive functions that impair the successful performance of daily living activities. Most forms of dementia are progressive in nature, increasing in severity over time, with the rate of symptoms progression and the age at onset differing among the major dementing disorders. The most frequent types of dementia include Alzheimer´s Disease (AD), Vascular Dementia, Dementia of Lewy bodies and Frontotemporal Dementia. Differential diagnosis of dementia is typically done by neuropsychological testing (for exclusion of other dementias) and neuroimaging investigations. However, many of the clinical symptoms typical of dementia may overlap across dementia subtypes, which may constitute a diagnosis problem leading to lack of specificity and misdiagnosis. Understanding the environmental and genetic factors that modulate risks and outcomes of diseases can open new perspectives on the management of these neurological disorders. Apolipoprotein E gene (ApoE) is recognized as the major genetic risk factor in dementia, in particular playing a central role in AD development, being that ApoE allele ε4 carriers are more susceptible to disease. Furthermore, putative associations have also been proposed between this gene and other neurological disorders, nonetheless controversial data have been reported regarding these aspect. Hence, the aim of this work was to determine ApoE genotypic and allelic frequencies in a pilot study group of dementing patients from the catchment area of the “Hospital de São Sebastião” in “Santa Maria da Feira”. This group was subdivided according to their neurochemical-based diagnosis of dementia, in which Aβ1-42, phospho-Tau 181 and total-Tau levels in patients’ cerebrospinal fluid were evaluated. In this study, we could observe that allele ε3 was the most frequent in the total study group, independent of the type of pathology, and that allele ε2 was the less frequent. Allele ε4 was in fact more frequent in AD patients than in other neurological disease patients, in agreement with the proposed link established by other authors. Additionally, we also find that allele ε4 frequency in patients suffering from amyloid pathology is similar to that observed in AD group, suggesting a role for ApoE in Aβ metabolism and brain accumulation. Potentially, these patients have a higher susceptibility to develop AD pathology in the future. Thus, our data supports the idea that ApoE allele ε4 is a strong risk factor for AD development and that it may be considered as a relevant genetic test that may assist in the clinical diagnosis of dementia.
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Lundbäck, Daniel. "Alkoholkonsumtion och episodiskt minne.Kan APOE genen vid olika konsumtionsnivåer ha betydelse?" Thesis, Stockholms universitet, Psykologiska institutionen, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-88448.
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I denna studie undersöktes om relationen mellan alkoholkonsumtion och episodiskt minne skiljer sig beroende på vilken allele av APOE genen en person har. Undersökningsdeltagarna delades upp i fyra grupper, medelålders män, medelålders kvinnor, äldre män och äldre kvinnor. Utbildningsnivå och ålder inom varje åldersgrupp användes som kovariat. APOE delades upp på 4 bärare och icke bärare. Några signifikanta interaktionseffekter mellan alkoholkonsumtion och APOE framkom inte i någon grupp. I gruppen medelåldersmän hittades en signifikant huvudeffekt av alkoholkonsumtion, där de som avstod från alkohol presterade sämre än de med olika nivåer av alkoholkonsumtion. Liknande tendenser syntes i de tre övriga grupperna där undersökningsdeltagare som avstod från alkohol presterade sämst, dock inte signifikant. En anledning till att de som konsumerar alkohol presterar bättre på episodiskt minnestest än de som inte dricker förmodas vara alkoholens positiva effekter på det kardiovaskulära systemet. Ytterligare forskning på området behövs då andra faktorer, så som hur mycket som dricks vid ett enskilt tillfälle, kan vara mer avgörande.Betula
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Gorman, Donal Neilson. "Triglycerides, the APOA5-APOC3 locus and coronary heart disease." Thesis, University of Cambridge, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.707967.
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Hua, Jennifer. "Rôle des récepteurs P2X4 dans la dégradation d’ApoE : implication dans la maladie d’Alzheimer." Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTT021/document.
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Les récepteurs purinergiques P2X4 (P2X4R) sont des récepteurs canaux exprimés par lesneurones et les microglies du système nerveux central et sont impliqués dans de nombreuxprocessus physiologiques et pathologiques. Des études préliminaires, menées au sein dulaboratoire, ont permis de mettre en évidence une interaction entre P2X4R etl’Apolipoprotéine E (ApoE), ainsi qu’une augmentation d’ApoE dans les macrophages et lesmicroglies provenant de souris déficientes pour P2X4R. Basée sur ces observations, lapremière partie de cette thèse a cherché à caractériser les mécanismes impliquant P2X4R danscet effet. ApoE étant un facteur de risque majeur dans la maladie d’Alzheimer, la deuxièmepartie de cette thèse a été consacrée à étudier l’implication de P2X4R dans cette pathologie.Les résultats présentés montrent que P2X4R module l’activité de la cathepsine B, enzymeresponsable de la dégradation lysosomale d’ApoE. L’utilisation de souris APP/PS1 a permisde montrer que l’absence de P2X4R conduit à une amélioration des capacités mnésiques, unediminution de la concentration de peptide Aβ soluble ainsi qu’à une augmentation d’ApoEmicrogliale.Ces résultats indiquent que P2X4R régule la dégradation d’ApoE par un mécanismedépendant de la cathepsine B, et que son invalidation permet d’améliorer les symptômescognitifs de la maladie d’AlzheimerP2X4 receptors (P2X4R) are purinergic ion channels expressed on neurons and microglia inthe central nervous system. They have been widely studied and have been implicated in manyphysiological and pathological processes. Previous studies conducted in the laboratoryrevealed an interaction between P2X4R and the Apolipoprotein E (ApoE), as well as anincrease in ApoE level in primary macrophages and microglia obtained from mice lackingP2X4R. Based on these results, this thesis aimed to decipher the mechanisms underlyingP2X4R regulation of ApoE levels. In addition, ApoE being a major risk factor forAlzheimer’s disease, part of this work investigated potential implications of P2X4R in thispathology.Results show that P2X4R modulates cathepsin B activity, which in turn promotes ApoElysosomal degradation. APP/PS1 mice lacking P2X4R show an increase in cognitiveperformances, a decrease in soluble Aβ peptide and an increase of microglia ApoE level.These results support that P2X4R modulates ApoE degradation in a cathepsin B-dependantmanner and that its invalidation leads to an improvement in Alzheimer’s pathology
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Hussain, Aseem. "Beneficial effects of estradiol are mediated through apoE /." View online, 2008. http://repository.eiu.edu/theses/docs/32211131425346.pdf.
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Trachtenberg, Aaron J. "The effects of APOE genotype on brain function." Thesis, University of Oxford, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.542982.
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Sleiman, Lyne. "The Role of cIAP2 in Early and Late Atherosclerosis Lesion Development." Thesis, Université d'Ottawa / University of Ottawa, 2011. http://hdl.handle.net/10393/20226.
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Cellular Inhibitor of Apoptosis 2 (cIAP2) belongs to the IAP family, a group of endogenous proteins that inhibit apoptosis. However, the physiological role of cIAP2 remains poorly defined. Knock-out (KO) and wild type (WT) mice were used to examine the effect of cIAP2 protein on the progression of atherosclerosis in apoE -/- mice. Following the high-fat diet period of 4 and 12 wks, tissues were harvested and analysis focused on the aortic root, the aortic arch, the descending aorta, and the blood. Ex vivo results show a significant decrease in aortic arch lesion area in KO vs. WT in both study groups. Results also show a decrease in aortic root lesion size in KO vs. WT in both study groups. These results support that cIAP2 is an important survival factor for lesion-associated macrophages, since loss of cIAP2 expression in this mouse model reduced atherosclerotic lesion development.
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Nielsen, Henrietta M., Kewei Chen, Wendy Lee, Yinghua Chen, Robert J. Bauer, Eric Reiman, Richard Caselli, and Guojun Bu. "Peripheral apoE isoform levels in cognitively normal APOE ε3/ε4 individuals are associated with regional gray matter volume and cerebral glucose metabolism." BIOMED CENTRAL LTD, 2017. http://hdl.handle.net/10150/622812.
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Background: Carriers of the APOE epsilon 4 allele are at increased risk of developing Alzheimer's disease (AD), and have been shown to have reduced cerebral metabolic rate of glucose (CMRgl) in the same brain areas frequently affected in AD. These individuals also exhibit reduced plasma levels of apolipoprotein E (apoE) attributed to a specific decrease in the apoE4 isoform as determined by quantification of individual apoE isoforms in APOE epsilon 4 heterozygotes. Whether low plasma apoE levels are associated with structural and functional brain measurements and cognitive performance remains to be investigated. Methods: Using quantitative mass spectrometry we quantified the plasma levels of total apoE and the individual apoE3 and apoE4 isoforms in 128 cognitively normal APOE epsilon 3/epsilon 4 individuals included in the Arizona APOE cohort. All included individuals had undergone extensive neuropsychological testing and 25 had in addition undergone FDG-PET and MRI to determine CMRgl and regional gray matter volume (GMV). Results: Our results demonstrated higher apoE4 levels in females versus males and an age-dependent increase in the apoE3 isoform levels in females only. Importantly, a higher relative ratio of apoE4 over apoE3 was associated with GMV loss in the right posterior cingulate and with reduced CMRgl bilaterally in the anterior cingulate and in the right hippocampal area. Additional exploratory analysis revealed several negative associations between total plasma apoE, individual apoE isoform levels, GMV and CMRgl predominantly in the frontal, occipital and temporal areas. Finally, our results indicated only weak associations between apoE plasma levels and cognitive performance which further appear to be affected by sex. Conclusions: Our study proposes a sex-dependent and age-dependent variation in plasma apoE isoform levels and concludes that peripheral apoE levels are associated with GMV, CMRgl and possibly cognitive performance in cognitively healthy individuals with a genetic predisposition to AD.
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Mukherjee, Sreya. "Applications of Molecular Modelling and Structure Based Drug Design in Drug Discovery." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6331.
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Calcium ions have important roles in cellular processes including intracellular signaling, protein folding, enzyme activation and initiation of programmed cell death. Cells maintain low levels of calcium in their cytosol in order to regulate these processes. When activation of calcium-dependent processes is needed, cells can release calcium stored in the endoplasmic reticulum (ER) into the cytosol to initiate the processes. This can also initiate formation of plasma membrane channels that allow entry of additional calcium from the extracellular milieu. The change in calcium levels is referred to as calcium flux. A key protein involved in initiation of calcium flux is Stromal Interaction Molecule 1 (STIM1), which has recently been identified as a sensor of ER calcium levels. STIM1 is an ER transmembrane protein that is activated by a drop in ER calcium levels. Upon activation, STIM1 oligomerizes with a plasma membrane protein, ORA1, to form calcium-selective plasma membrane channels. Dysregulation of calcium flux has been reported in cancers, autoimmune diseases and other diseases. STIM1 is a promising target in drug discovery due to its key role early in calcium flux. Here we review the involvement and importance of STIM1 in diseases and we discuss STIM1 as a viable target for drug discovery using computational chemistry methods to rapidly identify new molecules to target STIM1. Herein, computational techniques were used to understand the mechanistic role of STIM1 and virtual screening is in process to discover potential inhibitors of STIM1 activity. Also mutational analysis on STIM1 was performed computationally to see the effect it had on the protein computationally.
It has been found that tumor cells and tissues, compared to normal cells, have higher levels of copper and possibly other metal ions. This presents a potential vulnerability of tumor cells that can serve as a physiological difference between cancer cells and normal cells and allows design of compounds that selectively target tumor cells while sparing normal cells. Recently we have identified compounds that have potential to inhibit the proteasome in tumor cells and induce cell death by mobilizing endogenous tumor copper resulting in in cellulo activation of the compound. These compounds hence act as pro-drugs, becoming active drugs in tumor cells with high copper content but remaining essentially inactive in normal cells, thereby greatly reducing adverse effects in patients. Such use would be of significant benefit in early detection and treatment of cancers, in particular, aggressive cancers such as pancreatic cancer which is usually not detected until it has reached an advanced stage. Six compounds were identified following virtual screening of the NCI Diversity Set with our proteasome computer model followed by confirmation with a biochemical assay that showed significant inhibition of the proteasome by the compounds in the presence of copper ions. In a dose response assay, NSC 37408 (6, 7-dihydroxy-1-benzofuran-3-one), our best compound, exhibited an IC50 of 3µM in the presence of 100 nM copper.
Chagas’ Disease, a parasitic disease caused by the parasite Trypanosma Cruzi, is endemic to Latin America. The disease manifests itself in a short acute phase and a long chronic phase. Current treatments are effective only in the acute phase and are not used in the chronic phase due to toxicity of the drugs. Hence a new drug discovery approach was chosen for this disease. Cruzain is the major etiologic enzyme involved in the disease and is only present in the parasite. It is also an enzyme expressed by the parasite in both phases. Herein, a novel peptoid library containing hydromethylketones was constructed and screened against a virtual structure of cruzain. The peptoids thus found through this drug discovery effort can be used as potential drug candidates against cruzain. Computational techniques will help achieve a high degree of specificity and aid in proposing assays for determining compounds with high activity
Alzheimer disease is the most common form of dementia. Its pathogenesis incorporates many potential targets for treatment. Among the targets identified, Apolipoprotein E4 (apoE4) is especially interesting due to its catalytic role in the degradation and clearance of amyloid beta (Aβ), a risk factor for Alzheimer disease. ApoE exists in 3 isoforms which directly impact its functionality in the body. There are characteristic structural differences between them. In ApoE4 ionic interactions exist between Arg-61 and Glu-255 residues, unlike the other isoforms. Hence interruption of this interaction by inhibitors may change the structure of apoE4 to a more linear structure as observed in the other isoforms. Virtual screening of the NCI diversity set on an energy minimized protein virtual structure was performed to identify potential small molecule inhibitors and to gain further understanding of interactions that can be targeted to inhibit this protein. From the top ligands in the NCI diversity set, a peptide library was designed to target the protein.
Previous research has indicated that liquid assisted grinding (LAG) is efficient and reliable for cocrystal formation when compared to solvent crystallization and dimethyl formamide is the best solvent for grinding. Herein, we report the comparison of four screening processes: Slurry, solvent crystallization, LAG and dry grinding. Thirty-eight crystal forms containing the Narom··· COOH, Narom···OH supramolecular heterosynthons were screened in the process, and it was observed that slurry methodology is as efficient and reliable in forming cocrystals as solution crystallization. Twenty-four new crystal forms were also isolated herein. LAG was found to be more efficient as compared to dry grinding and was successful in the formation of twenty-five crystal forms of the thirty-eight screened. Dimethyl formamide still remains the best solvent for LAG. All our slurry experiments were performed in water and it was found that water can be used reliably for this method for compounds within a wide range of solubility, thereby increasing the versatility and usability of this method for future screening procedures.
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Coulombe, Jean-Denis. "Évaluer si le génotype de l'apolipoprotéine E influence l’absorption intestinale des acides gras." Mémoire, Université de Sherbrooke, 2017. http://hdl.handle.net/11143/11551.
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Introduction : L’apolipoprotéine E (ApoE) est une protéine membranaire impliquée dans le catabolisme des lipoprotéines riches en triglycérides (TG). Le polymorphisme du gène de l’apolipoprotéine E epsilon 4 (APOE4) est considéré comme le plus grand facteur de risque génétique de la maladie d’Alzheimer tardive. Il est connu que la consommation d’acide gras polyinsaturé oméga 3 (AGPI n-3) serait associée à une diminution du risque de déclin cognitif. L’acide docosahexaénoïque (DHA) est un AGPI n-3 contenu dans les poissons riches en gras. Des résultats publiés par la professeure Mélanie Plourde ont démontré que suite à une diète riche en DHA, la concentration plasmatique en DHA était 3 fois moins élevée chez les porteurs de l’APOE4. Cela laisse supposer que les porteurs d’APOE4 auraient possiblement une perturbation dans l’homéostasie des AGPI n-3 au niveau entérocytaire. Objectif : Déterminer le profil en acides gras (AG) dans le duodénum et le jéjunum selon la diète et le polymorphisme de l’APOE chez le modèle animal murin. Évaluer si la diète et/ou le polymorphisme de l’APOE affectent l’expression protéique des transporteurs d’AG dans le jéjunum chez le modèle animal murin. Matériel et méthodes : Des souris knock-in pour les différentes formes de l’APOE (APOE3 ou APOE4) ont été utilisées. À 4 mois, celles-ci ont reçu pendant 8 mois soit une diète contrôle ou une diète riche en DHA. Après sacrifice des animaux, le duodénum et le jéjunum ont été prélevés. Une extraction des lipides totaux par la méthode de Folch a été effectuée. Le profil en AG a ensuite été réalisé par chromatographie en phase gazeuse. L’expression protéique des transporteurs d’AG entérocytaire a été mesurée par immunobuvardage de type western. Résultats et discussion : Les souris nourries avec la diète DHA avaient une augmentation en DHA dans le duodénum et le jéjunum établissant ainsi que le DHA est bien absorbé par les entérocytes dans ce modèle animal. Le génotype de l’APOE ne semble pas affecter spécifiquement le métabolisme du DHA puisqu’aucune différence significative n’a été observée pour le génotype. Par ailleurs, les souris ayant consommé la diète DHA avaient une diminution en acide arachidonique. Cette diminution semble plus prononcée chez les souris porteuses de l’APOE4, ce qui pourrait suggérer une demande plus importante en DHA chez les souris porteuses de l’APOE4. D’autre part, les souris nourries avec la diète DHA avaient une augmentation significative de l’expression relative des transporteurs d’AG Cd36 et Fabp2. Finalement, le transporteur d’AG Fabp1 tend à être diminué chez les souris porteuses de l’APOE4 Conclusion : Ces résultats suggèrent une possible perturbation dans le transit et l’exportation des AG sous forme de chylomicron plutôt que dans l’absorption de ceux-ci.
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Ferguson, Chantal M. "Modulating ApoE with Tissue Specific siRNAs in Alzheimer’s Disease." eScholarship@UMMS, 2021. https://escholarship.umassmed.edu/gsbs_diss/1132.
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Among many putative genetic risk variations reported to date, the ApoE4 allele remains the most common genetic risk factor for late-onset AD, and is associated with both an increase in incidence and a decrease in age of clinical onset. The majority of ApoE is produced in the: 1) central nervous system (CNS) by astrocytes to transport lipids between cells and modulate the inflammatory response; and 2) liver, where it facilitates lipid uptake into peripheral tissues via low-density lipoprotein (LDL) receptors. Consistent with its dual roles, genetic knockout of ApoE increases the risk for atherosclerosis, but it also dramatically improves AD phenotypes in mouse models.
Antisense oligonucleotide (ASO) based modulation of CNS ApoE has only marginal effects on AD phenotypes, suggesting that post-embryonic silencing of ApoE is not a viable therapeutic strategy. However, the recent development of novel CNS siRNA chemical structures enables widespread distribution and potent target silencing throughout the brain. Using this technology, we demonstrate that liver and brain ApoE pools are spatially and functionally distinct, and that complete silencing of brain, not liver, ApoE results in robust reduction of amyloid plaque formation, without impacting systemic cholesterol. Furthermore, RNAseq analysis shows minimal off target effects of the siRNAs and identifies immune modulation and metabolic alterations as potential mechanisms behind ApoE’s role in plaque formation and clearance.
Moving forward, these results build upon the rationale to modulate ApoE expression and provide the technology necessary to further evaluate the impact ApoE silencing in AD and other neurodegenerative diseases
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Sinclair, Lindsey Isla. "Molecular and life-course aspects of APOE in cognition." Thesis, University of Bristol, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.701968.
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Dementia has a devastating effect on patients and those around them. Alzheimer's disease (AD) is the most common form of dementia. There is no cure and the prevalence may increase as much as fourfold by 2050. Variation in the APOE gene is the best-known genetic risk factor for AD. There is evidence to suggest that changes are evident in those with the high-risk Ɛ4 variant decades before AD develops. The exact nature of these changes, timing and their effect on brain structure and function is not clear. Another variant, the Ɛ2 variant seems to protect against AD but again the mechanism is unclear.
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Maioli, Silvia <1982>. "Interaction between APOE4 genotype and environmental risk factors in Alzheimer's disease." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2011. http://amsdottorato.unibo.it/3463/.
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Alzheimer's disease (AD) is probably caused by both genetic and environmental risk factors. The major genetic risk factor is the E4 variant of apolipoprotein E gene called apoE4. Several risk factors for developing AD have been identified including lifestyle, such as dietary habits. The mechanisms behind the AD pathogenesis and the onset of cognitive decline in the AD brain are presently unknown.
In this study we wanted to characterize the effects of the interaction between environmental risk factors and apoE genotype on neurodegeneration processes, with particular focus on behavioural studies and neurodegenerative processes at molecular level.
Towards this aim, we used 6 months-old apoE4 and apoE3 Target Replacement (TR) mice fed on different diets (high intake of cholesterol and high intake of carbohydrates). These mice were evaluated for learning and memory deficits in spatial reference (Morris Water Maze (MWM)) and contextual learning (Passive Avoidance) tasks, which involve the hippocampus and the amygdala, respectively. From these behavioural studies we found that the initial cognitive impairments manifested as a retention deficit in apoE4 mice fed on high carbohydrate diet. Thus, the genetic risk factor apoE4 genotype associated with a high carbohydrate diet seems to affect cognitive functions in young mice, corroborating the theory that the combination of genetic and environmental risk factors greatly increases the risk of developing AD and leads to an earlier onset of cognitive deficits.
The cellular and molecular bases of the cognitive decline in AD are largely unknown. In order to determine the molecular changes for the onset of the early cognitive impairment observed in the behavioural studies, we performed molecular studies, with particular focus on synaptic integrity and Tau phosphorylation. The most relevant finding of our molecular studies showed a significant decrease of Brain-derived Neurotrophic Factor (BDNF) in apoE4 mice fed on high carbohydrate diet. Our results may suggest that BDNF decrease found in apoE4 HS mice could be involved in the earliest impairment in long-term reference memory observed in behavioural studies.
The second aim of this thesis was to study possible involvement of leptin in AD. There is growing evidence that leptin has neuroprotective properties in the Central Nervous System (CNS). Recent evidence has shown that leptin and its receptors are widespread in the CNS and may provide neuronal survival signals. However, there are still numerous questions, regarding the molecular mechanism by which leptin acts, that remain unanswered.
Thus, given to the importance of the involvement of leptin in AD, we wanted to clarify the function of leptin in the pathogenesis of AD and to investigate if apoE genotype affect leptin levels through studies in vitro, in mice and in human.
Our findings suggest that apoE4 TR mice showed an increase of leptin in the brain. Leptin levels are also increased in the cerebral spinal fluid of AD patients and apoE4 carriers with AD have higher levels of leptin than apoE3 carriers. Moreover, leptin seems to be expressed by reactive glial cells in AD brains. In vitro, ApoE4 together with Amyloid beta increases leptin production by microglia and astrocytes. Taken together, all these findings suggest that leptin replacement might not be a good strategy for AD therapy. Our results show that high leptin levels were found in AD brains. These findings suggest that, as high leptin levels do not promote satiety in obese individuals, it might be possible that they do not promote neuroprotection in AD patients. Therefore, we hypothesized that AD brain could suffer from leptin resistance. Further studies will be critical to determine whether or not the central leptin resistance in SNC could affect its potential neuroprotective effects.
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ROSSI, K. B. "Participação da Apolipoproteína-e na Atividade Microbicida in Vitro Contra o Mycobacterium Tuberculosis." Universidade Federal do Espírito Santo, 2014. http://repositorio.ufes.br/handle/10/4582.
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Previous issue date: 2014-08-29A parede celular de Mycobacterium tuberculosis (Mtb) é constituída por 60% de lipídios, impedindo a passagem de uma grande quantidade de substâncias, além de desempenhar um importante papel na munopatogênese. A apresentação desses antígenos aos linfócitos se dá por meio de moléculas do tipo CD1. Por sua vez a Apolipoproteína-E (ApoE), glicoproteína amplamente distribuída nos tecidos, pode facilitar a apresentação de lipídios pelo CD1. A ApoE possui três principais alelos ApoE- 2, 3 e 4, que codificam três isoformas de proteínas, tipos 2, 3 e 4, que possuem diferentes estruturas e funções. A presença de determinadas isoformas da ApoE está associada a doenças infecciosas, como herpes labial, dano hepático severo causado pelo vírus da hepatite C, diarréia infantil e tuberculose pulmonar. Neste contexto, avaliamos a participação da ApoE na atividade microbicida in vitro frente ao Mtb. Para tanto, foram arrolados 13 indivíduos PPD-, 17 indivíduos PPD+ e 4 indivíduos com tuberculose pulmonar ativa. O uso de plasma humano depletado de ApoE nos experimentos de atividade microbicida in vitro mostraram um aumento significante (p=0,02) no número de micobactérias (431.5 ± 81.92 UFC) quando comparado ao grupo controle (313.0 ± 74.61 UFC). Esses resultados foram confirmados por um modelo experimental utilizando esplenócitos de camundongos de camundongos C57BL/6 (815.9 ± 76.32 UFC) e animais APOE nocaute (1133 ± 86.85 UFC) (p= 0.021). Quanto à produção de IL-10, no grupo PPD+, observamos que o grupo com depleção de ApoE (866.7 ± 447.8) apresentou uma produção menor desta citocina com relação ao controle infectado (1089 ± 481.3) (p=0,023). Já em relação ao IFN-, em ambos os grupos observou-se, após 72 horas, uma tendência à diminuição da produção dessa citocina no grupo com depleção, com relação ao grupo controle. Esses dados sugerem que a ApoE tem papel distinto na ativação da resposta imune e sua ausência pode prejudicar a resposta imune frente à tuberculose.
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Dancer, Marine. "Étude de la régulation de la triglycéridémie chez l’homme par des variants codants de LMF1 et non codants d’APOC3 et LMF1." Thesis, Lyon, 2017. http://www.theses.fr/2017LYSE1126/document.
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L'hyperchylomicronémie est une maladie rare et complexe impliquant plusieurs gènes qui sont eux-mêmes fortement régulés par plusieurs mécanismes et dont les voies métaboliques sont étroitement dépendantes de facteurs environnementaux. La survenue de la pathologie due à la présence de variants ou d'une association de variants sur ces gènes n'est pas toujours clairement définie. Ce qui suggère l'intervention d'autres mécanismes mal élucidés dans le développement des hyperchylomicronémies et la régulation du métabolisme des triglycérides. Nous avons essayé d'appréhender certains mécanismes causals dans la survenue de l hyperchylomicronémie en lien avec la présence de variants sur les gènes régulateurs APOC3 et LMF1 du métabolisme des triglycérides. Le gène APOC3 présente le variant SstI (rs5128) en région 3' non codante associée significativement à l'hypertriglycéridémie dans notre cohorte, nous avons cherché à caractériser sa régulation post-transcriptionnelle éventuelle par des microARN hépatiques ou intestinaux. Nos résultats ne confirment pas l'hypothèse d'une régulation du variant SstI du gène APOC3 par un microARN hépatique ou intestinal ciblant directement l'extrémité 3'UTR du gène APOC3. Le gène LMF1, nouveau gène candidat pour étudier les mécanismes des hyperchylomicronémies, est encore peu investigué. Nous avons mis en place son diagnostic génétique au sein du laboratoire ainsi qu'une technique in vitro permettant d'évaluer l'impact de la présence de certains variants codants de LMF1 sur l'activité post héparinique de la lipoprotéine lipase (LPL) par mesure de la lipolyse des triglycérides des VLDL. Nous avons mis en évidence des activités LPL significativement diminuées suggérant une dysfonction de LMF1 en présence des variants p.Gly172Arg (rs201406396), p.Arg354Trp (rs143076454), p.Arg364Gln (rs35168378), et des deux variants non-sens déjà décrits p.Tyr439Ter (rs121909397) et p.Trp464Ter (rs587777626). Ces travaux permettent de confirmer l'effet fonctionnel des variants LMF1 sur la régulation de la sécrétion de la LPL. Nous avons également retrouvé dans notre cohorte de 385 patients 18 variants sur la région 3' non codante du gène LMF1. Pour les trois variants : c*231C>A (rs75476513), c*512G>A (rs117039680), et c*530G>A (rs139657279), les résultats in vitro suggèrent une régulation post transcriptionnelle par les microARN. Ce qui pourrait ainsi expliquer le mécanisme de l'association de ces variants non traduits à l'hypertriglycéridémie. Ainsi, des interrelations des multiples gènes impliqués dans le métabolisme des triglycérides et leurs régulations à plusieurs niveaux simultanés modulent le phénotype d'hyperchylomicronémie. Il est nécessaire d'étudier tous les mécanismes complexes impliqués dans la régulation de la triglycéridémie afin de mieux appréhender la physiopathologie et de développer de nouvelles cibles thérapeutiquesHyperchylomicronemia is a rare and complex disease involving several genes which are themselves highly regulated by several mechanisms and whose metabolic pathways are closely dependent on environmental factors. The occurrence of this disease due to the presence of variants or a combination of variants on these genes is not always clearly defined. This suggests the intervention of other ill-defined mechanisms in the development of hyperchylomicronemia and the regulation of triglyceride metabolism. We have tried to understand certain causal mechanisms in the occurrence of hyperchylomicronemia in relation to the presence of variants on the APOC3 and LMF1 known regulatory genes of triglyceride metabolism. APOC3 gene carries the SstI variant (rs5128) in the 3' untranslated region significantly associated with hypertriglyceridemia in our cohort. We sought to characterize its possible post-transcriptional regulation by hepatic or intestinal microRNA. Our results obtained in vitro do not support the hypothesis of a regulation of the SstI variant of the APOC3 gene by a hepatic or intestinal microRNA directly targeting the 3'UTR of APOC3 gene. LMF1 gene, a new candidate gene for studying the mechanisms of hyperchylomicronaemias, is still under investigation. We have established its genetic diagnosis in the laboratory and set up an in vitro method to evaluate the impact of LMF1 coding variants by measuring the release of post-heparin lipoprotein lipase (LPL) activity. We found decreased LPL activities suggesting a LMF1 dysfunction in the presence of variants p.Gly172Arg (rs201406396), p.Arg354Trp (rs143076454), p.Arg364Gln (rs35168378), and the two nonsense variants already described p.Tyr439Ter (rs121909397) and p.Trp464Ter (rs587777626). This study confirms the functional effect of LMF1 variants on the regulation of LPL secretion. In addition, we found 18 variants on the 3' untranslated region of LMF1 gene. For three variants : c*231C>A (rs75476513), c*512G>A (rs117039680), and c*530G>A (rs139657279), in vitro results suggest a post-transcriptional regulation by microRNA. These findings are an involvement of these untranslated variants in the occurrence of hypertriglyceridemia.Thus, complex interrelations of multiple genes involved in triglyceride metabolism and their simultaneous multi-level regulation modulate the phenotype of hyperchylomicronemic patients. It is necessary to study all the complex mechanisms involved in the regulation of triglyceridemia in order to better understand pathophysiology of hyperchylomicronemia and to develop new therapeutic targets
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Dinkel, Regina Elke. "In-vivo Metabolismus der VLDL-Apolipoproteine ApoB, ApoCIII und ApoE." Diss., lmu, 2002. http://nbn-resolving.de/urn:nbn:de:bvb:19-3562.
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Wright, W. T. "Investigating the role of the APOC2, APOC3 and APOA5 genes in hypertriglyceridaemia." Thesis, Queen's University Belfast, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.403157.
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Harris, Julian David. "Development of recombinant adeno-associated virus and second generation adenovirus vectors for the gene transfer of human apolipoprotein E (ApoE) in the APOE deficient mouse." Thesis, Royal Holloway, University of London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.420867.
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Damy, Sueli Blanes. "Associação entre infecção experimental por Mycoplasma pneumoniae e/ou Chlamydophila (Chlamydia) pneumoniae e a intensidade das lesões ateroscleróticas da aorta, em camundongos C57BL/6 apoE KO, com ênfase na diferença entre os sexos." Universidade de São Paulo, 2006. http://www.teses.usp.br/teses/disponiveis/10/10133/tde-16042007-121022/.
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Os mecanismos pelos quais os agentes infecciosos, independentes ou não de meio ambiente permissivo, podem promover a aterogênese e as manifestações clínicas não estão completamente esclarecidos. Apesar das numerosas publicações demonstrando a presença de antígenos ou DNA de agentes infecciosos nas placas de ateroma, a questão se o agente infeccioso pode iniciar o processo aterosclerótico ou agravá-lo permanece sem resposta, possibilitando o aprofundamento das pesquisas neste assunto. Desta forma, este trabalho tem como objetivo estudar se a infecção experimental, por C.pneumoniae e/ou M.pneumoniae, em camundongos C57BL/6 apoE KO induziria ou afetaria a intensidade e a característica de vulnerabilidade da placa ateromatosa, de acordo com o sexo e/ou a dieta rica em colesterol. Métodos: um grupo de camundongos recebeu dieta enriquecida com 1% de colesterol (hiperlipidêmica), e o outro ração com formulação adequada para espécie (normolipidêmica), desde os dois meses de idade. Aos 8 meses de idade foram subdivididos, inoculados com 106 UFI de C.pneumoniae e/ou 106 UFC de M.pneumoniae, por via intraperitoneal, reinoculados um mês após e sacrificados aos 10 meses de idade. Para análise histopatológica secções transversais das aortas torácicas foram processadas para emblocamento em parafina, cortadas com 5 µm de espessura e coradas pelas técnicas de hematoxilina-eosina e tricrômico de Masson. As medianas das variáveis: altura da placa, área da placa, área de gordura da placa, área da artéria, área da luz e porcentagem de obstrução da luz da artéria dos diferentes grupos foram submetidas ao teste de Mann Whitney, com o nível de rejeição de 5%. Resultados: a infecção por C.pneumoniae e/ou M.pneumoniae causou agravamento da aterosclerose tanto em camundongos C57BL/6 apoE KO machos quanto em fêmeas. No entanto, as fêmeas infectadas somente com M.pneumoniae evoluíram com placas mais instáveis, representadas por maior remodelamento positivo. A co-infecção por C.pneumoniae e M.pneumoniae induziu placas mais estáveis, ou seja, com menor conteúdo de gordura e sem remodelamento, tanto nos machos quanto nas fêmeas. A introdução de dieta rica em colesterol levou ao não desenvolvimento de remodelamento positivo do vaso nas fêmeas infectadas por M.pneumoniae, mas sim nas co-infectadas por C.pneumoniae e M.pneumoniae que apresentaram placas mais instáveis, por serem mais volumosas e com maior conteúdo de gordura. Nos machos houve desenvolvimento de placas mais gordurosas nos infectados por C.pneumoniae. Conclusão: A infecção por C.pneumoniae e/ou M.pneumoniae em camundongos C57BL/6 apoE KO levou ao desenvolvimento ou agravamento de placas de aterosclerose, com diferenças em relação a intensidade e padrões de vulnerabilidade de acordo com o sexo versus o tipo de agente infecciosos. Os subgrupos infectados de fêmeas apresentaram maior agravamento da aterosclerose do que os machos. A dieta rica em colesterol agravou a intensidade da aterosclerose e mudou os padrões de vulnerabilidade dos subgrupos infectados.Independent of the presence or not a favorable ambient, mechanisms by which infectious agents may boost atherogenesis and clinical aspects are not fully elucidated. In spite of many demonstrations of infeccious agent antigens or DNA, the question if the infection may iniciate or aggravate the atherosclerotic process remains unanswered, requiring further studies. Therefore, the present work studies if the experimental infection of C57BL/6 apoE KO mice by C. pneumoniae and/or M. pneumoniae induces or affects the intensity of atherosclerosis and its characteristics of plaque vulnerability, with regard to the gender and/or the cholesterolrich diet. Methods: a group of mice was fed with 1% cholesterol-enriched diet (hyperlipidemic), from two months of age; the other group received adequately formulated food for the species (normolipidemic). At eight months of age, the mice were subgrouped according to inoculation intra-peritoneally with 106 IFU of C. pneumoniae and/or 106 CFU of M. pneumoniae, and re-inoculation one month later. They were killed at ten months of age. Cross-sectional thoracic aorta fragments were studied in embedded in paraffin block sections stained Hematoxylin-eosin and Masson?s trichromic techniques. Differences in the median of the variables: plaque height, plaque area, area of fat plaque, luminal area and percent obstruction of the lumen searched using the Mann Whitney?s test, with a 5% level of rejection. Results: the infection by C. pneumoniae and/or M. pneumoniae worsened atherosclerosis in both males and females C57BL/6 apoE KO mice. However, the M. pneumoniae inoculated female group presented more unstable plaques represented by positive remodeling of the vessel. The co-infection by both bacteria induced more stable plaque represented by low fat content and absence of vessel remodeling, in both male and female mice. The introduction of cholesterol enriched diet led to lack of positive vessel remodeling in M.pneumoniae inoculated female group, but development of unstable plaques characterized by large plaque are with high content of fat, in co-infected ones. In male groups there was development of plaque with higher fat content in the subgroup inoculated with C.pneumoniae. Conclusion: Infection by M. pneumoniae and/or C. pneumoniae, in C57BL/6 apoE KO mice, led to development or aggravation of atherosclerotic plaques, with differences regarding intensity and pattern of vulnerability according to the gender versus type of infectious agents. The infected female groups presented more aggravation of atherosclerosis than male ones. Cholesterol enriched diet aggravated the intensity of atherosclerosis and changed the patterns of vulnerability of infected subgroups.
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Martinic, Goran (Gary), of Western Sydney Hawkesbury University, of Science Technology and Environment College, and School of Environment and Agriculture. "Cyclodextrins as potential human anti-atherosclerotic agents." THESIS_CSTE_EAG_Martinic_G.xml, 2001. http://handle.uws.edu.au:8081/1959.7/129.
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Cyclodextrins (CDs) are naturally occurring cyclic oligosaccharides. Since it is believed that OxC blocks the removal of normal cholesterol from cells in the artery wall, it is possible that selective removal of OxC in the vessel wall in-vivo may prevent or reverse atherosclerosis.As a prelude to major studies, this research project was designed to answer two critical questions; 1/. What is the best route for delivery of CD. 2/. How do animals (apoE-/- mice) tolerate it. Pilot studies were established and results noted. These studies have provided valuable information in the apoE-/- mouse for subsequent studies to prevent or reverse atherosclerosis in this animal model.Master of Science (Hons)
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Larramona, Arcas Raquel. "ApoE4 pathology in Alzheimer’s disease from the perspective of organelle dysfunction in astrocytes." Doctoral thesis, Universitat Autònoma de Barcelona, 2018. http://hdl.handle.net/10803/666659.
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La enfermedad de Alzheimer es la forma mas común de demencia en edades avanzadas, la cual afecta a 40 millones de personas alrededor del mundo. Es una enfermedad compleja que afecta no solo a neuronas, sino también a astrocitos. La Apolipoproteína E4 (ApoE4) ha sido descrita como el factor de riesgo genético más importante de la forma esporádica de la enfermedad y además, los astrocitos son los principales secretores de esta. La investigación sobre los mecanismos patogénicos causados por esta apolipoproteína está centrada en su rol extracelular. Por el contrario, nosotros analizamos las desregulaciones intracelulares que causa la ApoE4. En nuestro estudio, nos centramos en 2 principales procesos fisiológicos alterados en la enfermedad de Alzheimer: la señalización de calcio y las funciones mitocondriales. Utilizamos como modelo celular, astrocitos inmortalizados que expresan la forma humana ApoE3 (no asociada a ninguna patología) o la ApoE4. Utilizando indicadores de calcio fluorescentes y la técnica de Imagen de Calcio, determinamos que los astrocitos ApoE4 tienen alteraciones de la homeostasis de calcio, ya que presentan menores niveles de calcio intracelular basal pero mayores señales de calcio inducidas por estímulos purinérgicos en comparación con los astrocitos ApoE3. Una mayor actividad de la V-ATPasa y por lo tanto, una mayor entrada de calcio al lisosoma en los astrocitos ApoE4 explica estas alteraciones. Además, la salida de calcio lisosomal después de la activación de receptores purinérgicos es seguida por una mayor movilización de calcio del retículo endoplásmico en los astrocitos ApoE4 comparados con los ApoE3. La entrada de calcio extracelular es similar en ambos tipos celulares. Nuestros estudios también demuestran que la falta de lipoproteínas en el medio extracelular aumenta la magnitud de las respuestas de calcio inducidas por receptores purinérgicos en los astrocitos ApoE3, ya que la entrada de calcio extracelular amplifica la liberación del calcio lisosomal en estas células. Esta característica se pierde en las células ApoE4, en las cuales la magnitud de las respuestas de calcio no se ve afectada por las lipoproteínas extracelulares. Por otro lado, describimos alteraciones en las dinámicas mitocondriales determinadas por microscopia a tiempo real y el marcaje fluorescente de mitocondrias. En particular, las mitocondrias de células ApoE4 no realizan fisión después de la inhibición de la fosforilación oxidativa mitocondrial, mientras que las mitocondrias de los astrocitos ApoE3 si la realizan. Asimismo, los astrocitos ApoE4 tienen un incremento en la movilidad mitocondrial, una reducción de Parkina, proteína involucrada en la mitofagia y una reducción del ADN mitocondrial en comparación con los astrocitos ApoE3. En resumen, demostramos por primera vez que la ApoE4 endógena altera la señalización del calcio y las funciones mitocondriales en astrocitos. Teniendo en cuenta que la ApoE4 se expresa a lo largo de toda la vida de los individuos, estas alteraciones astrocíticas podrían aparecer en las primeras etapas de la enfermedad de Alzheimer. Para avanzar en la detección de estas primeras etapas de la patología, y ya que las proteínas del líquido cefalorraquídeo reflejan las funcionalidad de las células cerebrales, nosotros hemos identificado un grupo de proteínas astrocíticas presentes en este líquido relacionadas con la enfermedad de Alzheimer y que proponemos como firma funcional astrocítica. Esta firma esta compuesta de las proteínas S100B, ApoE, prostaglandina D2 sintetasa, cistatina 3, proteína integral de membrana 2C y clusterina. En general, la ApoE4 endógena altera las funciones de los astrocitos, un fenómeno que puede contribuir a la enfermedad de Alzheimer, además de a su detección a través de biomarcadores del líquido cefalorraquídeo.Alzheimer’s disease is the most common form of dementia in advanced ages affecting more than 40 million people around the world. It is a complex disease that affects not only neurons but also astrocytes. Apolipoprotein E4 (ApoE4) has been described as the most important genetic risk factor for the sporadic form of the disease and interestingly, astrocytes are its main secretors. The research about its pathogenic mechanisms has mainly focused on its extracellular role. On the contrary, we analysed the dysregulations that endogenous intracellular ApoE4 causes on astrocytes. We focused on 2 principal physiological processes altered in Alzheimer’s disease: calcium signalling and mitochondrial functions. As cellular model, we used immortalized astrocytes that express human ApoE3 (non-associated with any pathology) or ApoE4. Using fluorescent calcium indicators and the technique of Calcium Imaging, we determined that ApoE4 astrocytes have altered calcium homeostasis as they have lower basal intracellular calcium levels but higher purinergic-induced calcium signals compared to ApoE3 astrocytes. A high V-ATPase activity, and hence, higher lysosomal calcium uptake in ApoE4 astrocytes explains these alterations. Moreover, lysosomal calcium release after purinergic receptor activation is followed by higher endoplasmic reticulum (ER) calcium mobilization in ApoE4 than in ApoE3 astrocytes. Extracellular calcium entry is similar in both cell types. Our studies also demonstrated that the lack of lipoproteins in the extracellular medium upregulates the magnitude of purinergic-elicited calcium responses in ApoE3 astrocytes, as extracellular calcium entry amplifies lysosomal calcium release. This feature is missing in ApoE4 astrocytes being the magnitude of calcium responses unaffected by extracellular lipoproteins. On the other hand, we described alterations in mitochondrial dynamics determined by real-time microscopy and fluorescent mitochondria labelling. In particular, ApoE4 cell mitochondria do not perform fission after inhibition of mitochondrial oxidative phosphorylation whereas ApoE3 astrocyte mitochondria perform it. In addition, ApoE4 astrocytes have increased mitochondrial motility, reduction of Parkin, a protein involved in mitophagy, and reduction in mitochondrial DNA content compared to ApoE3 astrocytes. In summary, we demonstrated, for the first time, that endogenous ApoE4 alters calcium signalling and mitochondrial functions in astrocytes. Taking into account that ApoE is expressed throughout the life of individuals, these astrocytic alterations might appear in the early stages of the Alzheimer’s disease. In order to advance in the detection of such early phases of the pathology, and since cerebrospinal fluid proteins reflect the cellular function of brain cells, we next identified a group of astrocytic proteins present in the cerebrospinal fluid related to Alzheimer’s disease that we propose as a functional astrocytic signature for early stages of the disease. This signature is composed of S100B, ApoE, prostaglandin D2 synthetase, cystatin 3, integral membrane protein 2C and clusterin. Overall, endogenous ApoE4 alters astrocyte functions, a phenomenon that can contribute to Alzheimer’s disease, but also, to its detection through cerebrospinal fluid biomarkers.
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Dumanis, Sonya Benjamina E. "Using APOE genotypes to identify new biomarkers for Alzheimer's disease risk." Thesis, Georgetown University, 2013. http://pqdtopen.proquest.com/#viewpdf?dispub=3559756.
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Alzheimer's disease (AD), unlike the other leading causes of death, does not have a cure or an effective intervention strategy. The largest genetic risk factor for AD is APOE, with the ϵ4 allele increasing and the ϵ2 allele decreasing one's risk for the disease. It remains unclear how ApoE isoforms contribute to various AD-related pathological changes (e.g. amyloid plaques, synaptic and neuron loss). Here, we characterize the differences between the at risk group for AD (the ϵ4 carriers) and the not-at risk group (non-ϵ4 carriers), to determine what underlies APOE-related risk to AD.
To do this, we utilized APOE Targeted Replacement (TR) mice. These animals express the human APOE alleles (APOE-ϵ2, APOE-ϵ3, or APOE-ϵ4) under the mouse APOE promoter, and do not develop the plaques and tangles diagnostic of AD. We found that despite the lack of AD pathology, APOE-ϵ4 TR mice had alterations at the synapse. Specifically, APOE-ϵ4 TR mice have fewer dendritic spines at the post-synaptic terminal and simpler neuronal morphology compared to the other APOE genotypes. Pre-synaptically, we found that APOE-ϵ4 TR mice have reduced levels of glutaminase, increased levels of VGLUT1 and increased levels of glutamine (GLN). Taken together, these data suggest that the APOE-ϵ4 allele affects brain function well before AD pathogenesis occurs.
To begin addressing the mechanism by which APOE can impact dendritic spine morphology, we examined the role of the apoE receptor, ApoEr2. We found that increased surface levels of ApoEr2 promoted dendritic spine formation and that the ligand binding domain is necessary for us to observe these effects, suggesting that ApoEr2 may be involved in APOE related changes at the synapse.
To test whether there are CSF biomarkers of APOE-associated risk that could be followed in preventative therapeutic AD approaches, we examined levels of GLN in ante-mortem CSF samples from healthy controls. Consistent with our mouse studies, we found that APOE-ϵ4 carriers had higher levels of GLN compared to the other genotypes. These studies suggest that GLN may be a novel biomarker used to assess AD patients in their pre-clinical phases and as a therapeutic measure in preventative AD trials.
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Obregon, Tito Alexandra de. "APOE haplotypes in health, lessons from an Oklahoman African American population." Oklahoma City : [s.n.], 2010.
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Naumann, Sandy. "Gen-Umweltinteraktion bei alkoholabhängigen Patienten am Beispiel von ApoE und Homocystein." kostenfrei, 2009. http://d-nb.info/999863649/34.
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Jiang, Qingguang. "The role of ApoE and liver X receptors in Alzheimer's disease." Cleveland, Ohio : Case Western Reserve University, 2008. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1212161307.
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Karpe, Britta. "Effekt von Darbepoetin alfa auf die geschädigte Niere am ApoE(-/-)-Mausmodell." kostenfrei, 2008. http://www.opus.ub.uni-erlangen.de/opus/volltexte/2008/1003/.
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Elam, Kit. "MEMORY AND DEFAULT NETWORK ACTIVATION AS A FUNCTION OF APOE GENOTYPE." OpenSIUC, 2010. https://opensiuc.lib.siu.edu/dissertations/204.
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The main purpose of this dissertation project was to assess the behavioral and neural correlates of Episodic Memory as a function of the APOE genotype in a healthy young adult sample. To accomplish this, 98 subjects completed behavioral tasks assessing visual memory, working memory, episodic memory, and attention. Subjects also completed questionnaires evaluating IQ, years of education, drug use, personality, and emotional traits. These subjects were also genotyped for the APOE gene, resulting in 29 APOE-ε4 carriers (subjects who had at least one ε4 allele) and 69 Non APOE-ε4 carriers (having no ε4 alleles). No differences were found between genotypic groups on any demographic characteristics, behavioral measures, or personality traits. From this larger pool of 98 subjects, a subset of 22 subjects (10 APOE-ε4, 12 Non APOE-ε4) completed additional behavioral tasks while undergoing functional magnetic resonance imaging. While being scanned, subjects were asked to learn word pairs during an encoding phase, make metamemory evaluations on their ability to later remember each word pair during a judgment of learning (JOL) task, and try to discriminate between original and recombined word pairs during a final recognition phase. Interspersed between these tasks was a rest task meant to elicit activity within the Default Network. No differences in memory or metamemory performance were found on the behavioral tasks administered during imaging based on genotype. In contrast, marked differences in brain activation were found between APOE-ε4 carriers and Non APOE-ε4 carriers across the various imaging tasks. During encoding, APOE-ε4 carriers were found to have greater activation than Non APOE-ε4 carriers in the dorsal anterior portion of the left superior temporal gyrus, cingulate gyrus, and anterior middle frontal gyrus. This same pattern - greater APOE-ε4 carrier activation as compared to Non APOE-ε4 carriers - was present in the parahippocampal gyrus and posterior middle temporal gyrus during the judgment of learning metamemory task. During the recognition task, greater activation was found for Non APOE-ε4 carriers versus APOE-ε4 carriers in the left parahippocampal gyrus, SPL, and right anterior superior frontal gyrus. During the rest task, greater activation was seen in APOE-ε4 carriers versus Non APOE-ε4 carriers in the left inferior frontal gyrus, whereas the converse comparison resulted in medial anterior cingulate activation. The lack of behavioral differences suggests that in a healthy young adult sample, as was used in the present study, there are not yet detectable behavioral differences as a function of APOE genotype. The greater neural activity seen in APOE-ε4 carriers during the encoding and judgment of learning tasks is likely to reflect neural compensation: young adult APOE-ε4 carriers compensate for declines in cognitive efficiency with greater neural activity such that this greater neural activity improves behavioral performance, particularly in memory domains (Buckner, Andrews-Hanna, & Schacter, 2008; Han & Bondi, 2008; Levy et al., 2004; Trivedi et al., 2008). The relatively lower levels of activation in APOE-ε4 carriers during the recognition task may reflect stronger memory traces for studied items as a result of greater frontal and medial temporal lobe activity during the encoding and judgment of learning tasks in the APOE-ε4 carriers (Kirwan, Wixted, & Squire, 2008; Mondadoori et al., 2007; Squire, Wixted, & Clark, 2007). In the present sample, a lack of behavioral differences accompanied by neural disparity may signal the precursors of Alzheimer's disease, highlighting the progressive deteriorating influence of the APOE-ε4 allele. The aberrant pattern of default network activity seen in APOE-ε4 carriers underlies this influence as this genotype is proposed to preferentially contribute to the causes of Alzheimer's disease in areas common to the Default Network and Episodic Memory (Buckner et al., 2008). The present results strengthen previous findings illustrating a connection between the brain activity underlying memory processes, the default network, and the APOE genotype.
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Young, Elizabeth. "HDL-apoE content regulates the cell surface displacement of hepatic lipase." Thesis, University of Ottawa (Canada), 2009. http://hdl.handle.net/10393/28247.
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Human hepatic lipase (HL) is an interfacial enzyme that must be liberated from cell surface proteoglycans to hydrolyze lipoprotein triglyceride. HDL and apolipoprotein (apo)A-1 can displace HL from cell surface proteoglycans, much like heparin. HL displacement is inhibited by HDL-apoE content. Postprandial HDL is ∼2-fold better at displacing HL than fasting HDL, but only has about half the apoE content. Enriching native HDL with triglyceride decreases HDL-apoE content and increases HL displacement. In contrast, enriching synthetic HDL with apoE significantly inhibits HL displacement. HDL from fasted female normolipidemic subjects displaces HL ∼2-fold better than HDL from male subjects. HDL from female subjects also has significantly less apoE than HDL from males. Normolipidemic females have increased circulating HDL-bound HL. Hyperlipidemia has little effect on the HL displacement ability of HDL from men, while HDL from hypercholesterolemic females exhibits impaired HL displacement. HL displacement from liver HSPG therefore appears to be linked to interlipoprotein apoE exchange. Decreased HL displacement is associated with higher HDL-apoE levels and may impact vascular triglyceride hydrolysis.
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Bott, Jean-Bastien. "Réorganisations synaptiques dans l'hippocampe et récupération fonctionnelle après lésion du cortex entorhinal : effets de l'allèle APOE4, du bourgeonnement cholinergique et de la réinnervation glutamatergique." Thesis, Strasbourg, 2014. http://www.theses.fr/2014STRAJ035/document.
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La maladie d’Alzheimer est souvent précédée de troubles cognitifs légers (MCI) associés à la lésion du cortex entorhinal, une région interconnecté avec l’hippocampe. Cependant, un tiers des patients MCI présentent une rémission cognitive suggérant l’action de mécanismes compensatoires. Ces mécanismes pourraient être déficitaires chez les patients porteurs de l’allèle APOE4 présentant un MCI plus agressif.Par des approches multidisciplinaires chez la Souris, ce travail a démontré que la lésion entorhinale induit des déficits comportementaux et une hyperactivité de l’hippocampe. Or, le bourgeonnement des fibres cholinergique dans l’hippocampe compense ces déficits. Comme le bourgeonnement cholinergique est inhibé en présence de l’APOE4, cela pourrait contribuer au déclin cognitif exacerbé de ces patients. Par conséquent, l’inhibition de l’hyperactivité hippocampique chez les 50% de patients APOE4 représente une alternative prometteuse pour le traitement symptomatique du MCIMild Cognitive Impairments (MCI) often precedes Alzheimer’s disease (AD) and is characterized by the loss of entorhinal neurons leading to a hippocampal disconnection. However, MCI patients also revert to normal cognition, suggesting compensatory mechanisms that alter the disease progression. This compensation may be impaired in patients bearing the APOE4 allele that are more prone to MCI, present less cognitive reversion and faster transition to AD.This work in mice, demonstrated that the sprouting of cholinergic fibers compensates entorhinal lesions through the reduction of the related hippocampal hyperactivity. As in APOE4 mice the cholinergic sprouting was altered in association with cognitive impairments, such impaired synaptic compensation may contribute to the faster cognitive decline of these patients. Therefore, supporting or mimicking the cholinergic control on hippocampal hyperactivity may represent a promising alternative therapeutic strategy for APOE4-carriers
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Xie, Ting. "Interactions épistatiques et modifications épigénétiques pour la stratification moléculaire des maladies chroniques." Thesis, Université de Lorraine, 2017. http://www.theses.fr/2017LORR0339/document.
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Les maladies chroniques, comme les maladies cardiovasculaires (MCV), la maladie d'Alzheimer (AD), la dépression et l'ostéoporose, sont les principales causes de mortalité dans le monde. L'identification de facteurs de risque communs à ces maladies pourrait contribuer à un vieillissement «sain» mieux surveillé en utilisant des stratégies personnalisées de prédiction des risques, de prévention précoce et de traitement adéquat, en tenant compte des comorbidités très souvent existantes. Dans cette thèse, 8 publications ont été développées. Dans un premier temps, j'ai résumé, dans un article de revue, les défis actuels et les opportunités de la pharmacogénomique des médicaments contre les maladies cardiovasculaires. J'ai participé à la formation d'un consortium international, le Consortium VEGF et j'ai participé à une étude qui a identifié des interactions épistasiques entre les polymorphismes qui régulent les niveaux de VEGF et la pression artérielle et les indices d'adiposité. J'ai également démontré qu’un marqueur génétique de VEGF, le rs4416670, était significativement associé à un risque accru de dépression. En outre, j'ai signalé deux interactions significatives entre les variantes liées au VEGF affectant la densité minérale osseuse du col fémoral chez les femmes ménopausées. J'ai également étudié deux marqueurs liés au métabolisme des lipides : l'apolipoprotéine E (APOE) et le «lipolysis-stimulated receptor» (LSR). J'ai trouvé que le variant LSR rs916147 peut interagir avec APOE d'une manière qui inverse l'effet protecteur de l'allèle ε2 de l'APOE sur les lipides sanguins, fournissant ainsi de nouvelles connaissances sur les mécanismes de l'hyperlipoprotéinémie de type III. Les interactions épistasiques entre ces deux gènes augmentent également le risque d’AD même en l'absence de l'allèle à risque, APOE ε4. Finalement, j'ai réalisé des études épigénetiques (EWAS) sur l'obésité centrale et les traits lipidiques chez des individus sains. Les résultats suggèrent qu'un CpG pourrait affecter le tour de taille à travers une voie de signalisation de l'insuline. En outre, deux CpGs ont été associées aux niveaux des triglycérides par des gènes liés aux maladies cardiaques génétiques (PRKAG2) et à l'inhibition de la signalisation Wnt / bêta-caténine impliquée dans le développement des MCV et d’AD (KREMEN2). En conclusion, dans cette thèse j’ai utilisé l'étude de l'épistasie et de l'épigénétique pour identifier des interrelations complexes entre VEGF, LSR, APOE et différentes maladies chroniques (MCV, AD, ostéoporose, dépression) proposant ainsi de nouveaux mécanismes et des dénominateurs communs de ces maladies qui devraient être utilisés comme biomarqueurs de médecine personnaliséeChronic diseases, like cardiovascular diseases (CVD), Alzheimer’s disease (AD), depression and osteoporosis, are major causes of mortality in the world. Identification of common to those diseases risk factors could help for a better-monitored ‘healthy’ aging, by promotion of personalised strategies for risk prediction, early prevention and adequate treatment, all taking into account the very often existing comorbidities. In this thesis, 8 publications have been developed. Initially, in a review paper, I have summarised the current challenges and opportunities of pharmacogenomics of CVD medications. I have participated in the formation of an international consortium, the VEGF Consortium, and I have participated in a study that identified significant epistatic interactions between polymorphisms that regulate the levels of VEGF and their effects on blood pressure and adiposity indexes. I have also demonstrated that one genetic marker of VEGF, rs4416670, was significantly associated with an increased risk for depression. Furthermore, I have reported two significant interactions between VEGF-related variants affecting the femoral neck bone mineral density in post-menopausal women. I have focused also on two markers linked with lipids metabolism: the apolipoprotein E (APOE) and the lipolysis-stimulated receptor (LSR). I have found that the LSR variant rs916147 can interact with APOE in a way that reverses the protective effect of the ε2 allele of APOE on blood lipids, thus providing new insights in the mechanisms underlying type III hyperlipoproteinemia. Epistatic interactions between these two genes have also been shown to increase the risk of AD, even in the absence of the known risk allele APOE ε4. Finally, I have performed epigenome-wide association studies (EWAS) on central obesity and blood lipid traits in healthy individuals. The results suggest that one methylation probe could affect waist circumference through an insulin-signaling pathway. Furthermore, two methylations probes were associated with triglycerides levels through genes linked with genetic heart diseases (PRKAG2) and with inhibition of the Wnt/beta-catenin signaling that is involved in CVD and AD development (KREMEN2). In conclusion, this thesis used the study of epistasis and epigenetics and identified complex inter-relationships between VEGF, LSR, APOE and different chronic diseases (CVD, AD, osteoporosis, depression) and novel mechanisms that link disease development with DNA methylation, thus demonstrating their role as common denominators of diseases that can be used as valuable markers in personalised medicine
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Giles, Brianna Elena. "Longitudinal Differences in White Matter Integrity Between APOE ε4 Carriers Versus Noncarriers." Thesis, The University of Arizona, 2015. http://hdl.handle.net/10150/579009.
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Alzheimer's disease (AD) is a neurodegenerative disorder that causes atrophy in gray and white matter (WM) as well as cognitive declines. Even though recent literature suggests that the apolipoprotein E (APOE) ε4 allele increases cognitive deficiencies in older adults, especially through increasing risk for the late-onset form of AD, relatively little is known about longitudinal differences in brain white matter integrity changes between APOE ε4 carriers and noncarriers. Data was obtained from 53 individuals (ages 55-91) which included 34 APOE ε4 noncarriers and 19 APOE ε4 carriers. From diffusion weighted images (DWI) fractional anisotropy (FA) maps were calculated at two time points 2.7 years apart, on average, in order to measure differences in the change in white matter integrity over time between the APOE ε4 groups. Regions of interest (ROI) were selected based on significant regions of difference at the first scan. No significant decreases in WM integrity were observed over time for the ROIs selected. However, in the left superior temporal white matter there was a significant increase in FA over time for the ε4 non-carriers but not the carriers. A similar, trending pattern was found in the left middle frontal white matter. Interestingly, these were two ROIs in which ε4 carriers had greater volumes at initial scan, suggesting that the regions of advantage with regard to white matter efficiency that ε4 carriers had compared to noncarriers disappear over time. Further analysis into associations between changes in white matter and changes in cognition over time should be undertaken.
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Filippini, Nicola. "Brain structure, function and connectivity associated with APOE genotype : what changes when?" Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.525306.
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Farsian, Farnas [Verfasser], and Jörg Heeren [Akademischer Betreuer]. "ApoE Regulates Corticospinal Neuronal Survival Through ApoER2 / Farnas Farsian. Betreuer: Jörg Heeren." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2013. http://d-nb.info/1045024538/34.
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McColl, Barry. "Pathophysiology of cerebral ischaemia : effects of APOE genotype on outcome and endocytosis." Thesis, University of Glasgow, 2004. http://theses.gla.ac.uk/4324/.
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Apolipoprotein E (apoE denotes protein: APOE denotes gene) is a lipid-transport protein abundantly expressed in the brain and strongly upregulated after acute brain injury. The APOE e4 allele is the major genetic risk factor for Alzheimer’s disease (AD) and has been associated with poorer outcome after various types of acute brain injury, including traumatic brain injury and subarachnoid haemorrhage. However, the role of APOE genotype in focal ischaemic stroke is less clear. The mechanism(s) by which APOE genotype may modulate outcome after acute brain injury are also unclear at present. Accordingly, the studies described in this thesis were undertaken to further address these issues. 1. Endocytic pathway alterations in human temporal lobe after global cerebral ischaemia and association with APOE genotype. 2. Characterisation and validation of the intraluminal filament model of focal cerebral ischaemia in C57BI/6J mice. 3. Association between APOE genotype and differences in outcome and endocytic pathway alterations after focal cerebral ischaemia in mice. 4. Adenovirus-mediated gene transfer of APOE e3 markedly reduces ischaemic brain damage after focal cerebral ischaemia in mice. The data presented in this thesis indicate an important role for APOE genotype in modulating outcome after ischaemic brain injury, further highlighting the favourable effects associated with the APOE e3 allele. APOE genotype-dependent alterations in the endocytic pathway are mechanisms which could contribute to differences in outcome. These data also highlight the neuroprotective effects achieved by manipulating apoE levels to promote the beneficial effects of apoE3. An apoE-based therapeutic strategy may be a potential approach for treatment of ischaemic brain injury in humans.
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Wu, Pei-Chi Coleman Rosalind A. "Will absence of GPAT1 improve diet-induced atherosclerosis in ApoE heterozygous mice?" Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2008. http://dc.lib.unc.edu/u?/etd,1933.
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Thesis (M.S.)--University of North Carolina at Chapel Hill, 2008.Title from electronic title page (viewed Dec. 11, 2008). "... in partial fulfillment of the requirement for the degree of Master of Science in the Department of Nutrition." Discipline: Nutrition; Department/School: Public Health.
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Stening, Eva. "The Influence of APOE ε4 on the Hippocampus and Hippocampus-Dependent Memory." Doctoral thesis, Uppsala universitet, Institutionen för psykologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-302855.
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APOE ε4 is the major genetic risk factor for Alzheimer’s disease, a dementia characterized by memory impairment and hippocampal atrophy. While associated with episodic impairment and reduced hippocampal volume in healthy aging, APOE ε4 has been related to increased episodic memory performance in young adults. The effect of APOE ε4 on hippocampal volume in young age is uncertain, with studies showing comparable or smaller volumes in ε4 carriers. This thesis aims to further explore the effects of APOE ε4 on episodic memory and hippocampal volume in young adults. In addition to episodic memory, spatial memory will also be assessed, as both these memory types are hippocampus-dependent. Furthermore, potential modulating effects of sex are assessed, as sex differences has been found in relation to APOE-related pathology, episodic and spatial memory and hippocampal volume. Study I examined the effects of APOE ε4 on episodic and spatial memory and hippocampal volume in young adults. Hippocampal volume was assessed by manual tracing of the hippocampal head, body and tail. Study II considered whole-brain structural covariance patterns of the anterior and posterior hippocampus. Furthermore, the association between these patterns and episodic and spatial memory performance was assessed. Study III investigated the effects of APOE ε4 on episodic and spatial memory and hippocampal volume in three different age groups. This was done in order to further explore the different effects of APOE ε4 on cognition and hippocampal volume seen in young and older age. In summary, APOE ε4 was positively associated with spatial function and episodic memory in young adults. Although there were no effects of APOE ε4 on hippocampal volume, structural covariance patterns of the anterior and posterior hippocampus differed as a function of APOE ε4 and sex. Thus, structural covariance may provide an early measure of APOE ε4-related effects on brain structure. Moreover, sex was found to modulate the effects of APOE ε4 to the disadvantage of women. This was seen in both age-related hippocampal volume effects and in structural covariance patterns in young adults, as well as in spatial memory performance across age groups.
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TAVARES, M. P. "A terapia com células mononucleares atenua a aterosclerose em camundongos ApoE Knockout." Universidade Federal do Espírito Santo, 2011. http://repositorio.ufes.br/handle/10/7964.
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Previous issue date: 2011-12-12As doenças cardiovasculares estão entre as maiores causas de morbidade e mortalidade no mundo. Dentre estas, destaca-se a aterosclerose, uma doença inflamatória crônica que acomete a parede de artérias de grande e médio calibre. Apesar das terapias convencionais, intervenções farmacológicas ou cirúrgicas, serem de grande valia, a terapia celular surge como uma nova estratégia terapêutica no tratamento e prevenção da aterosclerose. Dessa forma, este estudo tem como objetivo avaliar os efeitos da infusão de células mononucleares (CMN) sobre a evolução das lesões ateroscleróticas em camundongos knockout para o gene da apolipoproteína E (apoE KO). Camundongos apoE KO fêmeas com 6 meses de idade (n=16) e camundongos lacZ (animais transgênicos para -Galactosidase) foram utilizados nesse estudo. Os animais apoE KO receberam dieta hipercolesterolêmica (1,25% colesterol) para acelerar o processo de aterogênese por quatro meses. Aos quatro meses de idade, os animais eram divididos em dois grupos: 1) Grupo controle apoE KO e 2) Grupo que recebeu a terapia com CMN apoE KO-CMN. Os animais apoE KO-CMN receberam 8 infusões endovenosas de células mononucleares isoladas do baço de camundongos lacZ (106 células/semana). Após eutanásia, coletou-se o sangue para dosagem de colesterol plasmático, a artéria aorta foi removida para análise histoquímicas. Investigou-se a área de deposição lipídica, o remodelamento vascular, a expressão de óxido nítrico sintase endotelial (eNOS), a produção de ânions superóxido e a presença de células progenitoras endoteliais. Os dados estão expressos como média ± EPM e a análise estatística foi realizada por teste t de student ou ANOVA 1-via (*p<0,05). A análise histológica da aorta mostrou uma redução significativa na área de deposição lipídica nos animais que receberam a terapia celular (apoE KO-CMN) quando comparados ao grupo controle apoE KO (0,051* ± 0,004 vs 0,117 ± 0,016 mm2, respectivamente, *p <0,01). Além disso, a análise morfométrica revelou que a terapia com CMN impediu o remodelamento positivo dos animais apoE KO, normalmente observado (apoE KO-CMN: 0,98 ± 0,07 vs apoE KO: 1,37 ± 0,09), 13 utilizando animais selvagens (C57BL/6J) como referência. O grupo tratado com CMN também apresenta redução da produção de ânions superóxido e aumento da expressão da eNOS quando comparados aos animais apoE KO. Finalmente, a imunohistoquímica revelou uma migração de células progenitoras endoteliais (CPE) nas aortas dos animais apoE KO-CMN. Conclui-se que a terapia com CMN atenua a progressão da terosclerose em aortas de camundongos apoE KO. Nossos dados fornecem evidências de que o mecanismo pelo qual esta atenuação ocorre inclui a migração de CPEs, diminuição no estresse oxidativo e aumento da expressão de eNOS.
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Grace, Laurian Kerry. "The relationship between Alzheimer's disease, inflammation, the APOE genotype and neuronal integrity." Doctoral thesis, University of Cape Town, 2013. http://hdl.handle.net/11427/3394.
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Mathias, Daniel. "Auswirkungen niedrig dosierter ionisierender Strahlung auf inflammatorische Marker des ApoE-/- -Mäuse-Herzens." Doctoral thesis, Universitätsbibliothek Leipzig, 2017. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-221195.
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Die Akutfolgen ionisierender Strahlung wurden in zahlreichen Studien gut untersucht, ein Zusammenhang zwischen Hochdosisbestrahlung und deterministischen Spätschäden wurde vielfach belegt. Über die Langzeitfolgen niedrig dosierter ionisierender Strahlung hingegen ist bislang weniger bekannt, obwohl epidemiologische Studien auf ein erhöhtes Risiko strahlenassoziierter Spätfolgen hinweisen, sogar bei sehr geringen Dosen. Ionisierende Strahlung bedingt dosis- und zeitabhängigen Veränderungen in zahlreichen Geweben. Mittlere bis hohe Strahlendosen führen unter anderem zur strahleninduzierten koronaren Herzkrankheit mit ihren vielfältigen Folgeerkrankungen.
Die vorliegende Studie beschäftigt sich mit den inflammatorischen, thrombotischen und fibrotischen Spätfolgen des murinen ApoE-/- -Herzens 3 bzw. 6 Monate nach Niedrig-Dosis-Bestrahlung. Dazu wurde die Expression ausgewählter Markerproteine an gefroren Herzschnitten und Plasmaproben mittels Immunfluoreszenzanalyse bzw. ELISA quantifiziert. Es konnte gezeigt werden, dass bereits sehr niedrige Bestrahlungsdosen (0,025 – 0,5 Gy) zu kompensatorischen Langzeiteffekten wie beispielsweise einer erhöhte Kapillardichte und Änderungen von Kollagen-IV und Thy-1-Expression führen. Dabei finden sich sowohl pro- als auch antiinflammatorische Effekte.
Aus den Erkenntnissen multipler inflammatorischer und thrombotischer Veränderungen nach Niedrigdosisbestrahlung ließen sich möglicherweise wichtige Rationalen der anti-inflammatorischen Strahlentherapie ableiten. Darüber hinaus könnte anhand systemischer Plasmamarker die individuelle Evaluation strahlenassoziierter Spätfolgen und Einleitung adäquater Interventionsstrategien ermöglicht werden. Ob die hier gezeigten Effekte nur in Patienten mit besonderem Risikoprofil, wie erhöhten Cholesterin-Spiegeln, oder auch metabolisch gesunden relevant sind, bleibt weiteren Untersuchungen vorbehalten.
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Baba, Osamu. "MicroRNA-33 Deficiency Reduces the Progression of Atherosclerotic Plaque in ApoE-/- Mice." Kyoto University, 2014. http://hdl.handle.net/2433/188657.
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Coppens, Ryan Patrick. "ApoE4 Genotype as a Moderator of Brain Responses to Target Stimuli Prior and Subsequent to Smoking Abstinence." OpenSIUC, 2017. https://opensiuc.lib.siu.edu/dissertations/1494.
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A growing body of research is targeted towards characterizing and explaining nicotine’s complex interactions with the ApoE E4 allele on brain responses underlying cognitive processes. However, when and how the ε4 allele modulates neuroelectric brain responses in the presence of nicotine versus nicotine abstinence in nicotine-dependent smokers is not well characterized. Being able to understand this modulation is potentially quite important given that recent research implies that, relative to non-ε4 carriers, young adult carriers of the ε4 allele exhibit greater cognitive benefits from the use of nicotine. In the present study, electroencephalography (EEG) and the oddball-related P3b event-related potential (ERP) were used to better characterize the potential moderating effects of ApoE on P3b ERP amplitude changes associated with overnight nicotine deprivation in dependent smokers. Results showed a significant interaction between ApoE genotype and nicotine use, as ε4 carriers, relative to noncarriers, demonstrated significantly greater decreases following overnight deprivation, relative to prequit baseline levels. Additionally, there was a main of effect of P3b ERP amplitude to target stimuli being greater in ε4 allele carriers than in noncarriers during nicotine use, but no main effect of APOE genotype during overnight nicotine deprivation. These results are consistent with findings that the ApoE genotype moderates the effects of nicotine and alters neuroelectric brain responses associated with selective attention to infrequent target stimuli.
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GARCIA, Analia Nusya de Medeiros. "Polimorfismos dos genes CYP 46 e APOE e declínio cognitivo em idosos residentes no distrito de Fernando de Noronha-PE." Universidade Federal de Pernambuco, 2011. https://repositorio.ufpe.br/handle/123456789/8317.
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Previous issue date: 2011O Declínio Cognitivo Leve (DCL) é um estado mental considerado a zona de transição entre o envelhecimento normal e a fase mais inicial de demência, sendo uma fase importante para a precocidade diagnóstica. Nos últimos anos, pesquisas estão sendo desenvolvidas na busca de marcadores genéticos para esta zona de pré-demência, como os polimorfismos dos genes da apolipoproteína E (APOE) representada por 3 alelos (E2, E3, E4) e do colesterol 24S-hidroxilase (CYP46) com alelos T e C. Indivíduos portadores do APOE E4 tem fator de risco quatro vezes maior de desenvolver a Demência de Alzheimer e dez vezes mais probabilidade se tiver associado os polimorfismos dos genes APOE e CYP46. O objetivo deste estudo foi investigar a possível associação entre o polimorfismo dos genes CYP46(T/C), APOE E4 e a presença de DCL na população idosa do Distrito de Fernando de Noronha, totalizando uma seleção de 52 indivíduos. A avaliação clínica foi realizada através de exame físico, funcional e mental. Foram aplicados testes neuropsiquiátricos (Mini Exame do Estado Mental, Teste de Fluência Verbal, Teste do Relógio) e a identificação do genótipo dos polimorfismos do APOE e CYP46 pelo método de PCR-RFLP. Como resultados observou-se que 87% da amostra apresentou declínio cognitivo leve. No Mini Exame do Estado Mental, Teste de Fluência Verbal e Teste do Relógio foi observado declínio cognitivo em 42,8%, 31,9% e 53,2% respectivamente. Foi observada uma frequência alélica de 10% para o alelo E4. Não foi observada associação entre APOE E4 e declínio cognitivo. Os alelos T (p = 0,628) e C (p = 0,2076) do gene Cyp46 não estão associadas ao DCL na população estudada. Não foi observada associação (p = 0,4286), quando analisado o sinergismo entre o polimorfismo dos genes Cyp46(T/C) e APOE E4 no desenvolvimento do DCL. Nesta população, os resultados sugerem que os polimorfismos dos genes Cyp46(T/C) e APOE E4 não estão associados ao DCL