Toxoplasma gondii infection and peripheral-blood gene expression profiling of older people reveals dysregulation of cytokines and identifies hub genes as potential therapeutic targets.

Infections of humans with the protozoan parasite Toxoplasma gondii (T. gondii) can lead to the disease's development, even in an asymptomatic status. However, the mechanisms that result in these clinical outcomes after infection are poorly understood. This study aimed to explore the molecular pathogenesis of toxoplasmosis-related inflammation through next-generation sequencing, to assess RNA expression profiles in peripheral blood from 5 female patients with chronic toxoplasmosis and 5 healthy female controls. All plasma samples were analyzed for anti-Toxoplasma IgG and IgM antibody titers by using electrochemiluminescence. Detection of acute and chronic toxoplasmosis was carried out using the ELISA IgG avidity. We evaluated the levels of INF-γ, IL-2, IL-12, TNF-α, IL-10, and IL-1ß in culture supernatants of Peripheral Blood Mononuclear Cells infected with Toxoplasma lysate antigen (TLA) prepared with tachyzoites of strain T. gondii RH. Differential expression analysis was performed using DESeq2, pathway and enrichment analysis of DEGs was done on WEB-based Gene SeT AnaLysis Toolkit (WebGestalt) and Protein-protein interaction was carried out using NetworkAnalyst with STRING. In older people with chronic asymptomatic infection, a significant difference in the levels of inflammatory cytokines INF-γ and IL-2 was observed compared to seronegative individuals. Our results revealed differences in the regulation of critical biological processes involved in host responses to chronic T. gondii infection. Gene ontology analysis revealed several biologically relevant inflammatory and immune-related pathways.

Oestrogen receptor polymorphisms are an associated risk factor for mild cognitive impairment and Alzheimer disease in women APOE {varepsilon}4 carriers: a case-control study.

OBJECTIVES: Examine the role of single nucleotide polymorphisms (SNPs) in the oestrogen receptor (ER) genes: rs9340799, rs2234693, rs2228480 (in the ESR1 gene) and rs4986938 (in the ESR2 gene) as a risk factor for amnesic mild cognitive impairment (MCIa) and Alzheimer's disease (AD) and its possible association with the apolipoprotein E (APOE) gene. DESIGN: We have investigated the independent and combined association of different alleles of the oestrogen receptor genes and APOE*ε4 allele with cognitive impairment using a case-control design. SETTING: Participants were prospectively recruited from the neurology departments of several Basque Country hospitals. PARTICIPANTS: This study comprised 816 Caucasian participants who were aged 50 years and older: 204 MCIa, 350 sporadic patients with AD and 262 healthy controls. PRIMARY AND SECONDARY OUTCOME MEASURES: Clinical criteria and neuropsychological tests were used to establish the diagnostic groups (MCIa, AD and healthy controls). A dichotomous variable was used for each allele and genotype and the association with MCIa and AD was established using Logistic Regression Models. RESULTS: Neither alleles nor genotypes of SNPs rs9340799, rs2234693, rs2228480 and rs4986938 of oestrogen receptor genes (ESR1 and ESR2) are independently associated with the risk of MCIa or AD. However, the genetic profile created with the combination of the less represented alleles of these SNPs (expressed as XPAA) was associated with an increased risk for MCIa (OR=3.30, 95% CI 1.28 to 8.54, p=0.014) and AD (OR=5.16, 95% CI 2.19 to 12.14, p<0.001) in women APOE*ε4 allele carriers. CONCLUSIONS: The less represented alleles of SNPs studied are associated with MCIa and AD in APOE*E4 carriers. In particular, the genetic profile created with the less represented alleles of ESR1 and ESR2 SNPs are associated with an increased risk for MCIa and AD in women APOEε4 allele carriers.

[Role of genetics in the etiology of synucleinopathies]. / Papel de la genética en la etiología de las sinucleinopatías.

The protein family known as synucleins is composed of α-, ß- and γ-synuclein. The most widely studied is the α-synuclein protein due to its participation in essential processes of the central nervous system. Neurotoxicity of this protein is related to the presence of multiplications (duplications and triplications) and point mutations in the gene sequence of the α-synuclein gene (SNCA), differential expression of its isoforms and variations in post-transductional modifications. Neurotoxicity is also related to cytoplasmic inclusions known as Lewy bodies (LBs) and Lewy neurites (LNs), which are also present in α-synucleinopathies. In general, the ß-synuclein protein, codified by the SNCB gene, acts as a regulator of processes triggered by α-synuclein and its function is altered by variations in the gene sequence, while γ-synuclein, codified by the SNCG gene, seems to play a major role in certain tumoral processes.

Papel de la genética en la etiología de las sinucleinopatías / Role of genetics in the etiology of synucleinopathies

La familia de las proteínas conocidas como sinucleínas está compuesta por la α, la β y la γ-sinucleína. La proteína α-sinucleína es la más estudiada por su participación en procesos esenciales del sistema nervioso central. La neurotoxicidad de esta proteína está relacionada con la presencia de multiplicaciones (duplicaciones y triplicaciones) y mutaciones puntuales en la secuencia génica del gen de la α-sinucleína (SNCA), expresión diferencial de sus isoformas, así como variaciones en las modificaciones postransduccionales. Está relacionada con las inclusiones citoplasmáticas conocidas como cuerpos de Lewy y las neuritas de Lewy presentes también en las denominadas α-sinucleinopatías. En general, la proteína β-sinucleína codificada por el gen SNCB interviene como regulador de los procesos desencadenados por la α-sinucleína, viéndose alterada su función por variaciones en la secuencia génica, mientras que γ-sinucleína, codificada por el gen SNCG, parece jugar un papel transcendental en determinados procesos tumorales (AU)

The protein family known as synucleins is composed of α-, β- and γ-synuclein. The most widely studied is the α-synuclein protein due to its participation in essential processes of the central nervous system. Neurotoxicity of this protein is related to the presence of multiplications (duplications and triplications) and point mutations in the gene sequence of the α-synuclein gene (SNCA), differential expression of its isoforms and variations in post-transductional modifications. Neurotoxicity is also related to cytoplasmic inclusions known as Lewy bodies (LBs) and Lewy neurites (LNs), which are also present in α-synucleinopathies. In general, the β-synuclein protein, codified by the SNCB gene, acts as a regulator of processes triggered by α-synuclein and its function is altered by variations in the gene sequence, while γ-synuclein, codified by the SNCG gene, seems to play a major role in certain tumoral processes (AU)

Perfiles genéticos de longevidad y envejecimiento saludable en nonagenarios del País Vasco / Genetic profiles of longevity and healthy cognitive aging in nonagenarians from the Basque Country

Introducción. En la actualidad existen notables diferencias en el envejecimiento de los individuos de las poblaciones modernas. Mientras que algunos de ellos disfrutan de un prolongado envejecimiento saludable, otros desarrollan enfermedades neurodegenerativas como la enfermedad de Alzheimer (EA). Los factores ambientales son decisivos en este hecho, pero la genética puede contribuir a explicar las diferencias observadas. Recientemente se ha postulado que los genes de la longevidad podrían ser también neuroprotectores. Objetivos. Evaluar si determinadas variantes genéticas relacionadas con la longevidad pueden tener un carácter neuroprotector. Métodos. Los sujetos a estudio son las personas con una edad superior a 90 años. De cada participante se realizará la recogida de datos sociodemográficos, clínicos y múltiples valoraciones: cognitiva, funcional, antropométrica, nutricional, sensorial y física. Además, se realizará el análisis de 64 loci SNPs, distribuidos en 13 genes candidatos FOXO3, SIRT1, TOMM40, APOE, PICALM, COMT, CETP, CLU, CR1, IL-6, PCK-1, ZNF224 y ACE mediante Taqman array. Resultados. Obtener un mayor conocimiento sobre los alelos infra/sobre representados en las personas nonagenarias. Además, la comparación de las características genéticas de los nonagenarios con EA con aquellos libres de enfermedad permitirá observar vinculaciones entre determinados alelos con la protección o el riesgo de EA. La información asociada de los participantes permitirá crear subgrupos mostrando las interacciones entre el ambiente y las variaciones genéticas en relación al envejecimiento saludable y la EA. Conclusión. El estudio de la variabilidad genética de las personas nonagenarias nos puede dar información sobre los alelos relacionados con la longevidad y la neuroprotección(AU)

Introduction. Currently there are notable differences in the aging of individuals in modern populations. While some of them enjoy a long healthy aging, others develop neurodegenerative diseases, such as Alzheimer's disease (AD). Environmental factors are critical, but genetics could explain the differences observed. It has recently been postulated that longevity genes might also be neuroprotective. Objectives. To assess whether certain genetic variants associated with longevity might have a neuroprotective effect. Methods. The subjects of this study are people older than 90 years. We will collect sociodemographic and clinical data and multiple assessments, cognitive, functional, anthropometric, nutritional, sensory and physical each participant. In addition, 64 SNPs loci distributed in 13 candidate genes FOXO3, SIRT1, TOMM40, APOE, PICALM, COMT, CETP, CLU, CR1, IL-6, PCK-1, ZNF224 and ACE will be analysed by Taqman array. Results. It is hoped to gain more knowledge about under/over-represented alleles in nonagenarians. Furthermore, comparison of the genetic characteristics of nonagenarians with AD with those free of disease will enable links to be seen between certain alleles with protection or the risk of AD. Associated information on the participants will create subgroups showing the interactions between environment and genetic variation in relation to healthy aging and AD. Conclusion. The study of the genetic variability of nonagenarians can give us information on the alleles associated with longevity and neuroprotection(AU)

[Genetic profiles of longevity and healthy cognitive aging in nonagenarians from the Basque Country]. / Perfiles genéticos de longevidad y envejecimiento saludable en nonagenarios del País Vasco.

INTRODUCTION: Currently there are notable differences in the aging of individuals in modern populations. While some of them enjoy a long healthy aging, others develop neurodegenerative diseases, such as Alzheimer's disease (AD). Environmental factors are critical, but genetics could explain the differences observed. It has recently been postulated that longevity genes might also be neuroprotective. OBJECTIVES: To assess whether certain genetic variants associated with longevity might have a neuroprotective effect. METHODS: The subjects of this study are people older than 90 years. We will collect sociodemographic and clinical data and multiple assessments, cognitive, functional, anthropometric, nutritional, sensory and physical each participant. In addition, 64 SNPs loci distributed in 13 candidate genes FOXO3, SIRT1, TOMM40, APOE, PICALM, COMT, CETP, CLU, CR1, IL-6, PCK-1, ZNF224 and ACE will be analysed by Taqman array. RESULTS: It is hoped to gain more knowledge about under/over-represented alleles in nonagenarians. Furthermore, comparison of the genetic characteristics of nonagenarians with AD with those free of disease will enable links to be seen between certain alleles with protection or the risk of AD. Associated information on the participants will create subgroups showing the interactions between environment and genetic variation in relation to healthy aging and AD. CONCLUSION: The study of the genetic variability of nonagenarians can give us information on the alleles associated with longevity and neuroprotection.