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.

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

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.

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.

Made available in DSpace on 2016-08-29T15:34:59Z (GMT). No. of bitstreams: 1 tese_8103_Dissertação Kaymerê Final Corrigida.pdf: 1721673 bytes, checksum: 349a8b28df3024da428191034c651c47 (MD5) Previous issue date: 2014-08-29 / A 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.

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.

Alzheimer’s disease (AD) is a neurodegenerative disease classified pathologically by the presence of tau tangles and amyloid plaques. The largest genetic risk factor for AD is the APOE ε4 allele, while the APOE ε2 allele has been linked to a protective effect for AD. Recent studies demonstrated that APOE genotypes are linked to unique omics signatures and pathological features relating to AD, such as blood-brain barrier breakage. To investigate the role of APOE genotype in AD, I analyzed different levels of omic data in blood and brain. I analyzed transcriptomic data derived from autopsied brains using network and differential gene expression approaches to identify genes and pathways involved in the APOE ε2 protective mechanism for AD. Additionally, I identified APOE genotype-specific pathways and networks involved in both blood and brain function in AD using blood and brain tissue gene expression from mostly the same individuals. Lastly, I analyzed the association of methylation of DNA from blood and brain samples with AD to identify APOE and AD specific methylation signatures and potential drug targets. Collectively, this thesis emphasizes the utility of investigating APOE genotypes individually to identify novel pathways and potential drug targets within AD subpopulations.

TREM2 is an innate immune receptor expressed in microglia and macrophages. ApoE isoforms (E2/E3/E4) are ligands of TREM2. TREM2 variants and ApoE4 are top risk factors of Alzheimer’s disease. TREM2 can be cleaved from cell membrane as soluble TREM2 (sTREM2), the level of which fluctuates during Alzheimer’s progression. However, the mechanisms that sTREM2 and the interactions between TREM2 and ApoE may contribute to Alzheimer’s neuroinflammation are largely uncharacterized. The project objectives were to investigate whether sTREM2 and ApoE isoforms can affect cytokine expression profiles in myeloid-derived cell models. My results show that sTREM2 can stimulate inflammatory cytokine expression at early time-point but anti-inflammatory cytokine expression at later time-point mainly via MAPK-JNK signaling pathway. sTREM2 has differential effects on cytokine expression in M0, M1, and M2 macrophages. ApoE isoforms also differentially induce cytokine expression and regulate TREM2 expression in M0, M1, and M2 macrophages. My study reveals a complex interplay of sTREM2, TREM2 and ApoE isoforms and differential effects of those in the models.

No description available.

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’Alzheimer. / P2X4 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.