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Adult hippocampal neurogenesis is important for learning and memory and is altered early in Alzheimer's disease. As hippocampal neurogenesis is modulated by the circulatory systemic environment, evaluating a proxy of how hippocampal neurogenesis is affected by the systemic milieu could serve as an early biomarker for Alzheimer's disease progression. Here, we used an in vitro assay to model the impact of systemic environment on hippocampal neurogenesis. A human hippocampal progenitor cell line was treated with longitudinal serum samples from individuals with mild cognitive impairment, who either progressed to Alzheimer's disease or remained cognitively stable. Mild cognitive impairment to Alzheimer's disease progression was characterized most prominently with decreased proliferation, increased cell death and increased neurogenesis. A subset of 'baseline' cellular readouts together with education level were able to predict Alzheimer's disease progression. The assay could provide a powerful platform for early prognosis, monitoring disease progression and further mechanistic studies.
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Doença de Alzheimer , Disfunção Cognitiva , Adulto , Humanos , Doença de Alzheimer/metabolismo , Hipocampo/metabolismo , Aprendizagem , Disfunção Cognitiva/psicologia , Neurogênese/fisiologia , Progressão da DoençaRESUMO
BACKGROUND: Common variants in the TCF4 gene are among the most robustly supported genetic risk factors for schizophrenia. Rare TCF4 deletions and loss-of-function point mutations cause Pitt-Hopkins syndrome, a developmental disorder associated with severe intellectual disability. METHODS: To explore molecular and cellular mechanisms by which TCF4 perturbation could interfere with human cortical development, we experimentally reduced the endogenous expression of TCF4 in a neural progenitor cell line derived from the developing human cerebral cortex using RNA interference. Effects on genome-wide gene expression were assessed by microarray, followed by Gene Ontology and pathway analysis of differentially expressed genes. We tested for genetic association between the set of differentially expressed genes and schizophrenia using genome-wide association study data from the Psychiatric Genomics Consortium and competitive gene set analysis (MAGMA). Effects on cell proliferation were assessed using high content imaging. RESULTS: Genes that were differentially expressed following TCF4 knockdown were highly enriched for involvement in the cell cycle. There was a nonsignificant trend for genetic association between the differentially expressed gene set and schizophrenia. Consistent with the gene expression data, TCF4 knockdown was associated with reduced proliferation of cortical progenitor cells in vitro. LIMITATIONS: A detailed mechanistic explanation of how TCF4 knockdown alters human neural progenitor cell proliferation is not provided by this study. CONCLUSION: Our data indicate effects of TCF4 perturbation on human cortical progenitor cell proliferation, a process that could contribute to cognitive deficits in individuals with Pitt-Hopkins syndrome and risk for schizophrenia.
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Proliferação de Células/fisiologia , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/metabolismo , Células-Tronco Neurais/metabolismo , Fator de Transcrição 4/deficiência , Linhagem Celular , Córtex Cerebral/citologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Ontologia Genética , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Análise em Microsséries , Interferência de RNA , Esquizofrenia/genética , Fator de Transcrição 4/genéticaRESUMO
The biological activities of dietary bioactive polysaccharides have been largely explored. Studies on the immunomodulating effects of oligosaccharides and polysaccharides have shown that they are able to modulate innate immunity. Prebiotics are a class of poorly digested carbohydrates that are mainly produced from dietary fibers, which are carbohydrate polymers with ten or more monomeric units as defined by the Codex Alimentarius Commission in 2009. Considering the capacity of prebiotics in reducing gut inflammation, the aim of this study was to investigate the anti-inflammatory activity of galactooligosaccharide (Bimuno® GOS) in an in vitro model of ulcerative colitis (UC)-like inflamed intestinal cells. Differentiated Caco-2 cells were exposed to 2 % dextran-sulfate-sodium salt (DSS) to induce inflammation, and then with different concentrations of Bimuno GOS (1-1,000 µg/ml). Cell monolayer permeability, tight- and adherent junction protein distribution, pro-inflammatory cytokine secretion, and NF-kB cascade were assessed. Bimuno GOS at different concentrations, while not affecting cell monolayer permeability, was shown to counteract UC-like intestinal inflammatory responses and damages induced by DSS. Indeed, Bimuno GOS was able to counteract the detrimental effects of DSS on cell permeability, determined by transepithelial electrical resistance, phenol red apparent permeability, and tight- and adherent junction protein distribution. Furthermore, Bimuno GOS inhibited the DSS-induced NF-kB nuclear translocation and pro-inflammatory cytokine secretion. Further analyses showed that Bimuno GOS was able to revert the expression levels of most of the proteins involved in the NF-kB cascade to control levels. Thus, the prebiotic Bimuno GOS can be a safe and effective way to modulate the gut inflammatory state through NF-kB pathway modulation, and could possibly further improve efficacy in inducing remission of UC.
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OBJECTIVE: Frontotemporal lobar degeneration (FTLD) is the most common cause of early-onset dementia. Pathological ubiquitinated inclusion bodies observed in FTLD and motor neuron disease (MND) comprise trans-activating response element (TAR) DNA binding protein (TDP-43) and/or fused in sarcoma (FUS) protein. Our objective was to identify the causative gene in an FTLD-MND pedigree with no mutations in known dementia genes. METHODS: A mutation screen of candidate genes, luciferase assays, and quantitative polymerase chain reaction (PCR) was performed to identify the biological role of the putative mutation. Neuropathological characterization of affected individuals and western blot studies of cell lines were performed to identify the pathological mechanism of the mutation. RESULTS: We identified a nonpolymorphic mutation (c.672*51G>T) in the 3'-untranslated region (UTR) of the Sigma nonopioid intracellular receptor 1 (SIGMAR1) gene in affected individuals from the FTLD-MND pedigree. The c.672*51G>T mutation increased gene expression by 1.4-fold, corresponding with a significant 1.5-fold to 2-fold change in the SIGMAR1 transcript or Sigma-1 protein in lymphocyte or brain tissue. Brains of SIGMAR1 mutation carriers displayed a unique pathology with cytoplasmic inclusions immunopositive for either TDP-43 or FUS but not Sigma-1. Overexpression of SIGMAR1 shunted TDP-43 and FUS from the nucleus to the cytoplasm by 2.3-fold and 5.2-fold, respectively. Treatment of cells with Sigma-1 ligands significantly altered translocation of TDP-43 by up to 2-fold. INTERPRETATION: SIGMAR1 is a causative gene for familial FTLD-MND with a unique neuropathology that differs from other FTLD and MND cases. Our findings also suggest Sigma-1 drugs as potential treatments for the TDP-43/FUS proteinopathies.
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Degeneração Lobar Frontotemporal/genética , Doença dos Neurônios Motores/genética , Receptores sigma/genética , Idoso , Idoso de 80 Anos ou mais , Encéfalo/metabolismo , Encéfalo/patologia , Linhagem Celular Transformada , Proteínas de Ligação a DNA/metabolismo , Feminino , Degeneração Lobar Frontotemporal/metabolismo , Degeneração Lobar Frontotemporal/patologia , Haloperidol/farmacologia , Humanos , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/metabolismo , Doença dos Neurônios Motores/patologia , Mutação , Opipramol/farmacologia , Linhagem , Fenilacetatos/farmacologia , Pirrolidinas/farmacologia , Proteína FUS de Ligação a RNA/metabolismo , Receptores sigma/agonistas , Receptores sigma/antagonistas & inibidores , Receptores sigma/metabolismo , Receptor Sigma-1RESUMO
Myofibrillar myopathies (MFM) are heterogeneous hereditary muscle diseases with characteristic myopathological features of Z-disk dissolution and aggregates of its degradation products. The onset and progression of the disease are variable, with an elusive genetic background, and around half of the cases lacking molecular diagnosis. Here, we attempted to establish possible genetic foundations of MFM by performing whole exome sequencing (WES) in eleven unrelated families of 13 patients clinically diagnosed as MFM spectrum. A filtering strategy aimed at identification of variants related to the disease was used and included integrative analysis of WES data and human phenotype ontology (HPO) terms, analysis of muscle-expressed genes, and analysis of the disease-associated interactome. Genetic diagnosis was possible in eight out of eleven cases. Putative causative mutations were found in the DES (two cases), CRYAB, TPM3, and SELENON (four cases) genes, the latter typically presenting with a rigid spine syndrome. Moreover, a variety of additional, possibly phenotype-affecting variants were found. These findings indicate a markedly heterogeneous genetic background of MFM and show the usefulness of next generation sequencing in the identification of disease-associated mutations. Finally, we discuss the emerging concept of variant load as the basis of phenotypic heterogeneity.
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Age-related alteration in neural stem cell function is linked to neurodegenerative conditions and cognitive decline. In rodents, this can be reversed by exposure to a young systemic milieu and conversely, the old milieu can inhibit stem cell function in young rodents. In this study, we investigated the in vitro effect of the human systemic milieu on human hippocampal progenitor cells (HPCs) using human serum from early adulthood, mid-life and older age. We showed that neuroblast number following serum treatment is predictive of larger dentate gyrus, CA3, CA4 and whole hippocampus volumes and that allogeneic human serum from asymptomatic older individuals induced a two-fold increase in apoptotic cell death of HPCs compared with serum from young adults. General linear models revealed that variability in markers of proliferation and differentiation was partly attributable to use of antihypertensive medication and very mild cognitive decline among older subjects. Finally, using an endophenotype approach and whole-genome expression arrays, we showed upregulation of established and novel ageing molecular hallmarks in response to old serum. Serum from older subjects induced a wide range of cellular and molecular phenotypes, likely reflecting a lifetime of environmental exposures. Our findings support a role for the systemic enviroment in neural stem cell maintenance and are in line with others highlighting a distinction between neurobiological and chronological ageing. Finally, the herein described serum assay can be used by future studies to further analyse the effect of environmental exposures as well as to determine the role of the systemic environment in health and disease.
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BACKGROUND AND PURPOSE: Inflammation plays a prominent role in Alzheimer disease (AD) pathogenesis. Interleukin-6 (IL-6), a pro-inflammatory cytokine, and some genetic variations in the IL-6 gene have been reported to be associated with a risk of AD. However, the results of the conducted studies are equivocal. MATERIAL AND METHODS: We genotyped IL-6 (-174 C/G) and apolipoprotein E gene (APOE) common polymorphisms in a large case-controlled study in a Polish population. We included 361 patients aged ≥ 65 years with AD (mean age 75.8 ± 5.3 years, 232 females [64.3%]) and 200 controls (75.3 ± 7.4 years; 119 females [59.5%]), without any neurological deficit, cognitive complaints or history of neurological diseases. The IL-6 polymorphism was genotyped using TaqMan SNP allelic discrimination by means of an ABI 7900HT (Applied Biosystems, Foster City, CA). RESULTS: The distribution of the IL-6 (-174 C/G) genotypes was similar to that in the controls (AD: C/C = 15.79%, C/G = 51.25%, G/G = 32.96% vs. controls: C/C = 21.50%, C/G = 45.50%, G/G = 33.0%, p > 0.05). Our study confirms previous reports that APOE 4 is strongly related to the risk of AD (OR = 6.17; 95% CI: 4.01-9.49). APOE status did not affect the distribution of the studied IL-6 polymorphism. CONCLUSION: IL-6 (-174 C/G) polymorphism is not a risk factor for late onset AD in a Polish population.
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Doença de Alzheimer/genética , Apolipoproteínas E/genética , Interleucina-6/genética , Polimorfismo Genético , População Branca/genética , Idoso , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polônia , Regiões Promotoras Genéticas/genética , Fatores de RiscoRESUMO
BACKGROUND: Peptidyl-prolyl isomerase, NIMA-interacting 1 (PIN1) plays a significant role in the brain and is implicated in numerous cellular processes related to Alzheimer's disease (AD) and other neurodegenerative conditions. There are confounding results concerning PIN1 activity in AD brains. Also PIN1 genetic variation was inconsistently associated with AD risk. METHODS: We performed analysis of coding and promoter regions of PIN1 in early- and late-onset AD and frontotemporal dementia (FTD) patients in comparison with healthy controls. RESULTS: Analysis of eighteen PIN1 common polymorphisms and their haplotypes in EOAD, LOAD and FTD individuals in comparison with the control group did not reveal their contribution to disease risk.In six unrelated familial AD patients four novel PIN1 sequence variants were detected. c.58+64C>T substitution that was identified in three patients, was located in an alternative exon. In silico analysis suggested that this variant highly increases a potential affinity for a splicing factor and introduces two intronic splicing enhancers. In the peripheral leukocytes of one living patient carrying the variant, a 2.82 fold decrease in PIN1 expression was observed. CONCLUSION: Our data does not support the role of PIN1 common polymorphisms as AD risk factor. However, we suggest that the identified rare sequence variants could be directly connected with AD pathology, influencing PIN1 splicing and/or expression.
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Doença de Alzheimer/genética , Variação Genética , Peptidilprolil Isomerase/genética , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Peptidilprolil Isomerase de Interação com NIMA , Polimorfismo de Nucleotídeo Único , Regiões Promotoras GenéticasRESUMO
LGMD2L is a subtype of limb-girdle muscular dystrophy (LGMD), caused by recessive mutations in ANO5, encoding anoctamin-5 (ANO5). We present the analysis of five patients with skeletal muscle weakness for whom heterozygous mutations within ANO5 were identified by whole exome sequencing (WES). Patients varied in the age of the disease onset (from 22 to 38 years) and severity of the morphological and clinical phenotypes. Out of the nine detected mutations one was novel (missense p.Lys132Met, accompanied by p.His841Asp) and one was not yet characterized in the literature (nonsense, p.Trp401Ter, accompanied by p.Asp81Gly). The p.Asp81Gly mutation was also identified in another patient carrying a p.Arg758Cys mutation as well. Also, a c.191dupA frameshift (p.Asn64LysfsTer15), the first described and common mutation was identified. Mutations were predicted by in silico tools to have damaging effects and are likely pathogenic according to criteria of the American College of Medical Genetics and Genomics (ACMG). Indeed, molecular modeling of mutations revealed substantial changes in ANO5 conformation that could affect the protein structure and function. In addition, variants in other genes associated with muscle pathology were identified, possibly affecting the disease progress. The presented data indicate that the identified ANO5 mutations contribute to the observed muscle pathology and broaden the genetic spectrum of LGMD myopathies.
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Anoctaminas/ultraestrutura , Predisposição Genética para Doença , Músculo Esquelético/ultraestrutura , Distrofia Muscular do Cíngulo dos Membros/genética , Adulto , Anoctaminas/genética , Canais de Cloreto/genética , Biologia Computacional , Feminino , Heterozigoto , Humanos , Masculino , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/diagnóstico por imagem , Distrofia Muscular do Cíngulo dos Membros/patologia , Mutação/genética , Fenótipo , Polônia/epidemiologia , Adulto JovemRESUMO
Myofibrillar myopathy (MFM) is a group of inherited muscular disorders characterized by myofibril dissolution and abnormal accumulation of degradation products. The diagnosis of muscular disorders based on clinical presentation is difficult due to phenotypic heterogeneity and overlapping symptoms. In addition, precise diagnosis does not always explain the disease etiopathology or the highly variable clinical course even among patients diagnosed with the same type of myopathy. The advent of high-throughput next-generation sequencing (NGS) has provided a successful and cost-effective strategy for identification of novel causative genes in myopathies, including MFM. So far, pathogenic mutations associated with MFM phenotype, including atypical MFM-like cases, have been identified in 17 genes: DES, CRYAB, MYOT, ZASP, FLNC, BAG3, FHL1, TTN, DNAJB6, PLEC, LMNA, ACTA1, HSPB8, KY, PYROXD1, and SQSTM + TIA1 (digenic). Most of these genes are also associated with other forms of muscle diseases. In addition, in many MFM patients, numerous genomic variants in muscle-related genes have been identified. The various myopathies and muscular dystrophies seem to form a single disease continuum; therefore, gene identification in one disease impacts the genetic etiology of the others. In this review, we describe the heterogeneity of the MFM genetic background focusing on the role of rare variants, the importance of whole genome sequencing in the identification of novel disease-associated mutations, and the emerging concept of variant load as the basis of the phenotypic heterogeneity.
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Sequenciamento de Nucleotídeos em Larga Escala , Miopatias Congênitas Estruturais/genética , Análise Mutacional de DNA , Genômica , Humanos , Padrões de Herança , Proteínas Musculares/genética , Mutação , FenótipoRESUMO
A critical role of mitochondrial dysfunction and oxidative damage has been implicated in etiopathology of many neurodegenerative disorders, as well as in normal aging. Alzheimer's and Parkinson's diseases are common devastating late-onset neurodegenerative disorders, associated with mitochondrial DNA variations, which are suggested to affect mitochondrial functions. This paper reviews the current knowledge on the inherited and somatic mtDNA variations in both conditions.
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Doença de Alzheimer/etiologia , Doença de Alzheimer/genética , DNA Mitocondrial/genética , Doença de Parkinson/etiologia , Doença de Parkinson/genética , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
The hippocampus is one of the earliest affected brain regions in Alzheimer's disease (AD) and its dysfunction is believed to underlie the core feature of the disease-memory impairment. Given that hippocampal volume is one of the best AD biomarkers, our review focuses on distinct subfields within the hippocampus, pinpointing regions that might enhance the predictive value of current diagnostic methods. Our review presents how changes in hippocampal volume, shape, symmetry and activation are reflected by cognitive impairment and how they are linked with neurogenesis alterations. Moreover, we revisit the functional differentiation along the anteroposterior longitudinal axis of the hippocampus and discuss its relevance for AD diagnosis. Finally, we indicate that apart from hippocampal subfield volumetry, the characteristic pattern of hippocampal hyperactivation associated with seizures and neurogenesis changes is another promising candidate for an early AD biomarker that could become also a target for early interventions.
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Alterations in hippocampal neurogenesis have been recognized as an integral part of Alzheimer's disease. Adult hippocampal neurogenesis is regulated by intrinsic and extrinsic factors; one of them is diet. This review provides an assessment of the current state of the field in hippocampal neurogenesis studies in Alzheimer's disease and focuses on the role of diet. The review highlights some of the key dietary compounds and interventions such as calorie restriction, fat, polyphenols, zinc, folate, alcohol and thiamine, and emphasizes the pathways that they modify.
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Doença de Alzheimer/dietoterapia , Doença de Alzheimer/patologia , Dieta , Hipocampo/fisiologia , Neurogênese/fisiologia , Restrição Calórica , HumanosRESUMO
Polymorphic, deoxythymidine-tract in intron 6 of the TOMM40 gene has been associated with Alzheimer's disease. We have investigated the impact of this polymorphism on Parkinson's disease risk and age of onset, independently and in combination with apolipoprotein E alleles, in a group of 407 PD patients and 305 control subjects. No significant association was observed at the single allele, genotype, or haplotype levels. Our data suggest that the polymorphism is not a risk factor for Parkinson's disease in the Polish population.
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Apolipoproteínas E/genética , Proteínas de Membrana Transportadoras/genética , Doença de Parkinson/genética , Polimorfismo Genético , Idade de Início , Alelos , Estudos de Casos e Controles , Genótipo , Haplótipos , Humanos , Íntrons/genética , Pessoa de Meia-Idade , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Doença de Parkinson/epidemiologia , Polônia/epidemiologia , Fatores de RiscoRESUMO
Interactions of transcriptions factors Nurr1, Pitx3, and EN1 are involved in the maturation and survival of adult midbrain dopaminergic neurons during a lifetime. The aim of the study was to evaluate the presence of mutations and single nucleotide polymorphisms in PITX3 gene in clinically diagnosed multisystem atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). In the group of 77 patients with MSA, 44 with PSP, and 6 with CBD, no pathogenic mutations were identified.
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Proteínas de Homeodomínio/genética , Atrofia de Múltiplos Sistemas/genética , Doenças Neurodegenerativas/genética , Paralisia Supranuclear Progressiva/genética , Fatores de Transcrição/genética , Idoso , Gânglios da Base/patologia , Córtex Cerebral/patologia , Primers do DNA/genética , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Doenças Neurodegenerativas/patologia , Polônia , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
In this study we evaluated biochemical blood serum parameters and the association of Cyclin-dependent kinase 5 (CDK5) gene polymorphisms with the risk of Alzheimer's disease (AD) in the Polish population. We observed an elevated total cholesterol, low-density lipoproteins (LDL) and homocysteine levels and lower concentrations of high-density lipoproteins (HDL) and vitamin B12 in AD patients. However, the analyzed CDK5 polymorphisms were not associated with the biochemical parameters. Moreover, we found no association between the studied polymorphisms and the risk of AD in the Polish population. The meta-analysis of previously published and current study was performed. In conclusion, our study demonstrated that alteration of cholesterol, LDL, HDL, homocysteine and B12 concentration may be an important factor in pathogenesis of AD.
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Doença de Alzheimer/sangue , Doença de Alzheimer/genética , Quinase 5 Dependente de Ciclina/sangue , Quinase 5 Dependente de Ciclina/genética , Polimorfismo Genético/genética , Apolipoproteínas E/genética , Feminino , Ácido Fólico/sangue , Estudos de Associação Genética , Genótipo , Homocisteína/sangue , Humanos , Lipídeos/sangue , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Riboflavina/sangueRESUMO
Recently, it has been reported that TOMM40 variable-length poly-T sequence polymorphism (rs10524523) in combination with APOE alleles (E2, E3, E4) significantly influences late-onset Alzheimer's disease (LOAD) age of onset. In a group of 414 LOAD patients, 173 centenarians and 305 neurologically healthy individuals, we investigated the impact of TOMM40 poly-T tracts on LOAD incidence, age of onset, and longevity. TOMM40 allelic variants were classified into four categories: short (S; 14-16T), long a (La; 20-22T), long b (Lb; 26-30T), and very long (VL; 31-39T). Our results demonstrate that La and Lb share similar characteristics in affecting LOAD risk, thus for some analyses they were combined into L category. We observed significantly lower frequency of VL allele (p < 0.0001) and significantly higher frequency of L alleles in the LOAD patients compared to the control individuals (p < 0.0001). S/S, S/VL, and VL/VL genotypes and VL-E2, S-E3, VL-E3 haplotypes are significantly associated with lower LOAD risk. VL-E3 haplotype carriers significantly more frequently developed LOAD when they were ≥79 years old. Additionally, S/L genotype is associated with a significantly increased LOAD risk (p < 0.0001). We conclude that in the carriers of TOMM40-APOE haplotypes comprising E4 allele, the TOMM40 rs10524523 allele does not play substantial role in establishing LOAD risk. Nevertheless, TOMM40 L allele increases the risk when E4 is absent. Finally, L allele, as well as genotypes (S/L, V/L) and haplotypes (L-E3, L-E4) comprising L significantly reduce the likelihood of living up to 100 years.
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Doença de Alzheimer/genética , Predisposição Genética para Doença/genética , Longevidade/genética , Proteínas de Membrana Transportadoras/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Apolipoproteínas E/genética , Distribuição de Qui-Quadrado , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Proteínas do Complexo de Importação de Proteína Precursora MitocondrialRESUMO
To date, one of the most discussed hypotheses for Alzheimer's disease (AD) etiology implicates mitochondrial dysfunction and oxidative stress as one of the primary events in the course of AD. In this review we focus on the role of mitochondria and mitochondrial DNA (mtDNA) variation in AD and discuss the rationale for the involvement of mitochondrial abnormalities in AD pathology. We summarize the current data regarding the proteins involved in mitochondrial function and pathology observed in AD, and discuss the role of somatic mutations and mitochondrial haplogroups in AD development.
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Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Apolipoproteína E4/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Apolipoproteína E4/genética , Encéfalo/metabolismo , Encéfalo/patologia , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Humanos , Mitocôndrias/genética , Mitocôndrias/patologiaRESUMO
We investigated the potential contribution of mitochondrial DNA (mtDNA) variants, haplogroups, and polymorphisms in nuclear genes essential for mitochondrial biogenesis and function (PGC-1α TFAM) to late-onset Alzheimer's disease (LOAD) risk. Epistatic interaction analysis was conducted between the studied variables. Our results demonstrate that mtDNA haplogroups and subhaplogroups with putative role in partial uncoupling of oxidative phosphorylation are significantly associated with a decreased LOAD risk (OR <1). Conversely, mtDNA haplogroup H (p = 0.049) and HV cluster (p = 0.018) are significant LOAD risk factors, which was additionally confirmed by meta-analysis (OR = 1.22, OR = 1.25, respectively). Haplogroup K was demonstrated to exert a neutralizing effect on the high risk associated with APOE4+ status (p = 0.014). Further, two synergistic interactions between subhaplogroup H5 and APOE4 status (p = 0.009) and between TFAM rs1937 and APOE4 status (p < 0.001) were detected, influencing LOAD risk. No interaction pointing to a dual mitochondrial-nuclear genome variation effect on LOAD occurrence was identified.
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Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Proteínas de Ligação a DNA/genética , Variação Genética/genética , Proteínas de Choque Térmico/genética , Proteínas Mitocondriais/genética , Fatores de Transcrição/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/genética , Mitocôndrias/patologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Fosforilação/genética , Fatores SexuaisRESUMO
The mitochondrial transcription factor A (TFAM) has been recently shown to decrease reactive oxygen species (ROS) generation. It is also known that mitochondrial DNA (mtDNA) haplogroups might confer different coupling properties, resulting in different ROS levels. We hypothesized that potentially functional TFAM variants could influence PD risk depending on haplogroup background. To test this we assessed the role of six TFAM variants on PD risk in 326 PD patients and 316 controls, and correlated it with mtDNA haplogroup clusters (HV, JTKU and a putative functionally different group U4U5a1KJ1cJ2, connected previously with partial uncoupling of oxidative phosphorylation). Both genotype and haplotype analysis showed that intronic variant rs2306604 modifies PD risk. Multivariate logistic regression analysis confirmed that rs2306604 G/G genotype is an independent risk factor for PD (OR 1.789, 95% CI 1.162-2.755, p=0.008). There was a borderline interaction between G/G genotype and HV haplogroup (p=0.075). Haplotype analysis showed that all three haplotypes containing rs2306604 allele A occurred at higher frequencies in controls, but only one of them reached statistical significance (chi(2) 4.523, p=0.0334). Conversely, four of five haplotypes containing allele G had higher frequencies in PD group, with no statistical significance.