Overrepresentation of glutamate signaling in Alzheimer's disease: network-based pathway enrichment using meta-analysis of genome-wide association studies.

Genome-wide association studies (GWAS) have successfully identified several risk loci for Alzheimer's disease (AD). Nonetheless, these loci do not explain the entire susceptibility of the disease, suggesting that other genetic contributions remain to be identified. Here, we performed a meta-analysis combining data of 4,569 individuals (2,540 cases and 2,029 healthy controls) derived from three publicly available GWAS in AD and replicated a broad genomic region (>248,000 bp) associated with the disease near the APOE/TOMM40 locus in chromosome 19. To detect minor effect size contributions that could help to explain the remaining genetic risk, we conducted network-based pathway analyses either by extracting gene-wise p-values (GW), defined as the single strongest association signal within a gene, or calculated a more stringent gene-based association p-value using the extended Simes (GATES) procedure. Comparison of these strategies revealed that ontological sub-networks (SNs) involved in glutamate signaling were significantly overrepresented in AD (p<2.7×10(-11), p<1.9×10(-11); GW and GATES, respectively). Notably, glutamate signaling SNs were also found to be significantly overrepresented (p<5.1×10(-8)) in the Alzheimer's disease Neuroimaging Initiative (ADNI) study, which was used as a targeted replication sample. Interestingly, components of the glutamate signaling SNs are coordinately expressed in disease-related tissues, which are tightly related to known pathological hallmarks of AD. Our findings suggest that genetic variation within glutamate signaling contributes to the remaining genetic risk of AD and support the notion that functional biological networks should be targeted in future therapies aimed to prevent or treat this devastating neurological disorder.

Wnt/ß-catenin signaling in Alzheimer's disease.

Alzheimer's disease is a neurodegenerative disorder that causes a progressive decline of mental and cognitive processes such as memory, judgment and reasoning. We proposed earlier that a sustained loss of function of Wnt/ß- catenin signaling components underlies the onset and progression of the disease. Here, we discuss recent data on the involvement of Wnt/b-catenin signaling on amyloid precursor protein (APP) processing, Aß peptide neurotoxicity, τ phosphorylation, and modulation of Apolipoprotein E function in the brain. We conclude that several components of the cascade are actively engaged in the events leading to AD neuropathology and propose that compounds that mimic activation of this signaling cascade, such as lithium, should be considered for therapeutic intervention in Alzheimer's patients. In summary, data accumulated during the past decade confirm some important predictions of our hypothesis where components of this signaling cascade are actively engaged in the events leading to AD neuropathology and that compounds that mimic activation of this signaling cascade, such as lithium, should be considered for therapeutic intervention in Alzheimer's patients.

A novel functional low-density lipoprotein receptor-related protein 6 gene alternative splice variant is associated with Alzheimer's disease.

We previously found that single nucleotide polymorphisms in the low-density lipoprotein receptor-related protein 6 (LRP6) gene are associated with Alzheimer's disease (AD). Here, we studied the posttranscriptional metabolism of the LRP6 message scanning sequentially the 23 LRP6 exons in human tissues and found a novel LRP6 isoform that completely skips exon 3 (LRP6Δ3) in all tissues examined and was also conserved in mice. Expression levels of the LRP6 isoforms were determined in 47 cortical brain messenger (m)RNA samples including 22 AD cases, 11 control subjects, and 14 individuals with other neurological disorders. LRP6Δ3 mRNA levels were significantly augmented in AD brains compared with controls (1.6-fold; p = 0.037) or other pathological samples (2-fold; p = 0.007). Functional analysis in Wnt/ß-catenin signaling assays revealed that skipping of exon 3 reduced significantly the signaling activity of the LRP6 coreceptor. We conclude that the LRP6Δ3 isoform is a novel splice variant, which shows diminished Wnt/ß-catenin signaling activity and might have a functional role in individuals with AD.

Fractions of aqueous and methanolic extracts from tomato (Solanum lycopersicum L.) present platelet antiaggregant activity.

Cardiovascular disease (CVD) is the leading cause of death worldwide. Its prevention emphasizes three aspects: not smoking, physical activity and a healthy diet. Recently, we screened the antithrombotic activity of a selected group of fruits and vegetables. Among them, tomato showed an important effect. The aim of this study was to evaluate and characterize the platelet antiaggregatory activity of tomato (Solanum lycopersicum L.). For this, we obtained aqueous and methanolic tomato extracts and evaluated the effect of pH (2 and 10) and temperature (22, 60 and 100°C) on this activity. Furthermore, in order to isolate the antiaggregant principle, we separated tomato extracts into several fractions (A-D) by size exclusion chromatography. In addition, we evaluated the platelet antiaggregating activity ex vivo in Wistar rats. Aqueous and methanolic extracts of tomato treated at 22, 60 and 100°C and pH 2 and 10 still inhibited platelet aggregation (in vitro). Moreover, it was noted that one of the fractions (fraction C), from both aqueous and methanolic extracts, presented the highest activity (∼70% inhibition of platelet aggregation) and concentration dependently inhibited platelet aggregation significantly compared with control (P < 0.05). These fractions did not contain lycopene but presented two peaks of absorption, at 210 and 261 nm, compatible with the presence of nucleosides. In rats treated with tomato macerates, a mild platelet antiaggregating effect ex vivo was observed. Further studies are required to identify the molecules with platelet antiaggregating activity and antiplatelet mechanisms of action.

[High prevalence of classic cardiovascular risk factors in a population of university students from south central Chile]. / Alta prevalencia de factores de riesgo cardiovascular clásicos en una población de estudiantes universitarios de la región centro-sur de Chile.

INTRODUCTION AND OBJECTIVES: Cardiovascular disease is the principle cause of death worldwide. Such disease can be prevented by controlling cardiovascular risk factors. METHODS: The study involved 783 students aged between 18 and 26 years from the University of Talca (Region VII, Maule, Chile), which corresponds to 14.9% of all students. Their demographic characteristics, familial cardiovascular disease history, weight, height, arterial pressure, and waist diameter were recorded, and their lipid and blood glucose levels were measured. RESULTS: Overall, 12.8% of students had some degree of arterial hypertension, which was more severe in men than in women (P<.0001). In addition, 45.5% of the men and 24.3% of the women were overweight or obese. Some 39.8% of students admitted being smokers and 91.5% did not participate in any significant physical activity. Hypercholesterolemia (>or=200 mg/dL) was present in 20.2% of students and around 1.0% had the metabolic syndrome. CONCLUSIONS: The prevalence of the main cardiovascular risk factors was found to be high in the study population. It may be necessary to carry out regular publicity campaigns that focus on improving lifestyle to decrease the prevalence of cardiovascular risk factors in young people in whom morbidity and mortality is still low.

Alta prevalencia de factores de riesgo cardiovascular clásicos en una población de estudiantes universitarios de la región centro-sur de Chile / High prevalence of classic cardiovascular risk factors in a population of university students from south central Chile

Introducción y objetivos. Las enfermedades cardiovasculares (ECV) son la primera causa de muerte en el mundo. Dichas enfermedades se pueden prevenir mediante el control de los factores de riesgo cardiovascular. Métodos. Se estudió a 783 alumnos entre 18 a 26 años de edad de la Universidad de Talca (VII Región del Maule, Chile), lo que equivale al 14,9% del alumnado. Se registraron sus datos demográficos, los antecedentes familiares de enfermedad cardiovascular, el peso, la talla, la presión arterial y el diámetro de cintura, y se determinaron su perfil lipídico y su glucemia. Resultados. El 12,8% de los alumnos presentó algún grado de hipertensión arterial, que fue mayor en varones que en mujeres (p < 0,0001). El 45,5% de los varones y el 24,3% de las mujeres presentaron sobrepeso u obesidad. El 39,8% de los estudiantes se reconoció fumador y el 91,5% no realizaba ninguna actividad física significativa. El 20,2% del alumnado presentó una colesterolemia de 200 mg/dl y alrededor del 1% de los alumnos presentó síndrome metabólico. Conclusiones. En la población estudiada se encontró una alta prevalencia de los principales factores de riesgo cardiovascular. Parece necesario establecer campañas focalizadas y periódicas que tengan como objetivo mejorar los estilos de vida (disminuir la prevalencia de factores de riesgo cardiovascular) en jóvenes que aún no expresan morbimortalidad

Introduction and objectives. Cardiovascular disease is the principle cause of death worldwide. Such disease can be prevented by controlling cardiovascular risk factors. Methods. The study involved 783 students aged between 18 and 26 years from the University of Talca (Region VII, Maule, Chile), which corresponds to 14.9% of all students. Their demographic characteristics, familial cardiovascular disease history, weight, height, arterial pressure, and waist diameter were recorded, and their lipid and blood glucose levels were measured. Results. Overall, 12.8% of students had some degree of arterial hypertension, which was more severe in men than in women (P=200 mg/dL) was present in 20.2% of students and around 1.0% had the metabolic syndrome. Conclusions. The prevalence of the main cardiovascular risk factors was found to be high in the study population. It may be necessary to carry out regular publicity campaigns that focus on improving lifestyle to decrease the prevalence of cardiovascular risk factors in young people in whom morbidity and mortality is still low