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1.
Brain Behav Immun ; 69: 35-47, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29258921

RESUMO

Several studies suggest a link between shifts in gut microbiota and neurological disorders. Recently, we reported a high prevalence of Helicobacter suis (H. suis) in patients with Parkinson's disease. Here, we evaluated the effect of gastric H. suis infection on the brain in mice. One month of infection with H. suis resulted in increased brain inflammation, reflected in activation of microglia and cognitive decline. Additionally, we detected choroid plexus inflammation and disruption of the epithelial blood-cerebrospinal fluid (CSF) barrier upon H. suis infection, while the endothelial blood-brain barrier (BBB) remained functional. These changes were accompanied by leakage of the gastrointestinal barrier and low-grade systemic inflammation, suggesting that H. suis-evoked gastrointestinal permeability and subsequent peripheral inflammation induces changes in brain homeostasis via changes in blood-CSF barrier integrity. In conclusion, this study shows for the first time that H. suis infection induces inflammation in the brain associated with cognitive decline and that the choroid plexus is a novel player in the stomach-brain axis.


Assuntos
Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Plexo Corióideo/metabolismo , Mucosa Gástrica/metabolismo , Infecções por Helicobacter/metabolismo , Inflamação/metabolismo , Animais , Barreira Hematoencefálica/microbiologia , Encéfalo/microbiologia , Quimiocinas/metabolismo , Plexo Corióideo/microbiologia , Citocinas/metabolismo , Infecções por Helicobacter/microbiologia , Inflamação/microbiologia , Camundongos , Estômago/microbiologia
2.
Mol Psychiatry ; 18(11): 1225-34, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23399914

RESUMO

Genome-wide association studies (GWAS) have identified a region upstream the BIN1 gene as the most important genetic susceptibility locus in Alzheimer's disease (AD) after APOE. We report that BIN1 transcript levels were increased in AD brains and identified a novel 3 bp insertion allele ∼28 kb upstream of BIN1, which increased (i) transcriptional activity in vitro, (ii) BIN1 expression levels in human brain and (iii) AD risk in three independent case-control cohorts (Meta-analysed Odds ratio of 1.20 (1.14-1.26) (P=3.8 × 10(-11))). Interestingly, decreased expression of the Drosophila BIN1 ortholog Amph suppressed Tau-mediated neurotoxicity in three different assays. Accordingly, Tau and BIN1 colocalized and interacted in human neuroblastoma cells and in mouse brain. Finally, the 3 bp insertion was associated with Tau but not Amyloid loads in AD brains. We propose that BIN1 mediates AD risk by modulating Tau pathology.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Predisposição Genética para Doença/genética , Proteínas Nucleares/genética , Proteínas Supressoras de Tumor/genética , Proteínas tau/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Doença de Alzheimer/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Proteínas de Drosophila/deficiência , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Endofenótipos , Expressão Gênica/genética , Humanos , Camundongos , Degeneração Neural/genética , Degeneração Neural/patologia , Proteínas Nucleares/biossíntese , Placa Amiloide/patologia , Polimorfismo de Nucleotídeo Único/genética , Sinaptossomos/patologia , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/biossíntese , Proteínas tau/antagonistas & inibidores
3.
Mol Psychiatry ; 18(4): 461-70, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22430674

RESUMO

Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 × 10(-10)). We finally searched for association between SNPs within the FRMD4A locus and Aß plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Aß42/Aß40 ratio (best signal, P=5.4 × 10(-7)). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Doença de Alzheimer/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Haplótipos/genética , Doença de Alzheimer/sangue , Peptídeos beta-Amiloides/sangue , Estudos de Casos e Controles , Humanos , Polimorfismo de Nucleotídeo Único/genética
4.
Mol Psychiatry ; 17(2): 223-33, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21403675

RESUMO

Two multicentre genome-wide association (GWA) studies provided substantial evidence, implicating the complement receptor 1 gene (CR1) in Alzheimer disease (AD) genetic etiology. CR1 encodes a large transmembrane receptor with a crucial role in the immune complement cascade. We performed a genetic follow-up of the GWA CR1 association in a Flanders-Belgian cohort (n=1883), and investigated the effect of single-nucleotide polymorphisms (SNPs) located in the CR1 locus on AD risk and cerebrospinal fluid (CSF) biomarker levels. We obtained significant association (P(adj)<0.03; odds ratio (OR)=1.24 (95% confidence interval (CI): 1.02-1.51)) for one CR1 risk haplotype, and haplotype association was strongest in individuals carrying apolipoprotein E (APOE) ɛ4 alleles (P(adj)<0.006; OR=1.50 (95% CI: 1.08-2.09)). Also, four SNPs correlated with increased CSF amyloid Aß1₋42 levels, suggesting a role for the CR1 protein in Aß metabolism. Moreover, we quantified a low-copy repeat (LCR)-associated copy number variation (CNV) in CR1, producing different CR1 isoforms, CR1-F and CR1-S, and obtained significant association in carriers of CR1-S. We replicated the CR1 CNV association finding in a French cohort (n=2003) and calculated in the combined cohorts, an OR of 1.32; 95% CI: 1.10-1.59 (P=0.0025). Our data showed that the common AD risk association may well be explained by the presence of CR1-S increasing the number of C3b/C4b and cofactor activity sites and AD risk with 30% in CR1-S carriers. How precisely the different functional role of CR1-S in the immune complement cascade contributes to AD pathogenesis will need additional functional studies.


Assuntos
Doença de Alzheimer/genética , Fator I do Complemento/metabolismo , Variações do Número de Cópias de DNA/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Complemento/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteína E4/genética , Estudos de Coortes , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Modelos Logísticos , Masculino , Metanálise como Assunto , Razão de Chances , Fragmentos de Peptídeos/líquido cefalorraquidiano , Duplicações Segmentares Genômicas , Proteínas tau/líquido cefalorraquidiano
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