Apolipoproteína E e a doença de Alzheimer

It is known that polymorphisms in the gene of the apolipoprotein E (apoE) are important risk factors in the development of the Alzheimer's disease (AD). The human gene apoE, which is mapped in the long arm of chromosome 19 (19q13.2), codes for a glycoprotein with 317 amino acids, which plays a basic role for the catabolism of triglyceride-rich components in the human body. In our species the apoE gene appears in the form of three main alleles, produced from two alterations in the DNA sequence, called epsilon2, epsilon3 and epsilon4. The identification of the variant epsilon4 of gene apoE as the most relevant genetic marker for the risk for late-onset AD suggests that cholesterol may have a direct involvement in the patho­genesis of this disease. However, apoE epsilon4 is not necessary nor enough to cause Alzheimer's disease. It only increases the risk of an individual to develop the illness, indicating that other environmental/genetic factors shoud play important roles in the development of the disease.Sabemos hoje que os polimorfismos no gene da apolipoproteína E (apoE) são importantes fatores de risco para o desenvolvimento da doença de Alzheimer (DA). O gene apoE humano, mapeado no braço longo do cromossomo 19 (19q13.2), codifica uma glicoproteína com 317 aminoácidos, a qual desempenha um papel fundamental para o catabolismo de componentes ricos em triglicérides no corpo humano. Em humanos, existem três alelos principais do gene apoE, decorrentes de apenas duas alterações no DNA, chamados de épsilon2, épsilon3 e épsilon4. A identificação da variante épsilon4 do gene apoE como o fator genético de risco mais comum para a DA de início tardio sugere que o colesterol deva ter um papel direto na patogênese da doença. Contudo, a simples presença do alelo apoE épsilon4 não é necessária nem suficiente para causar DA; este alelo apenas aumenta o risco de o indivíduo vir a desenvolver a doença, indicando que existem outros fatores ambientais e genéticos importantes no desenvolvimento da mesma

Alterações genéticas na doença de Alzheimer

With the increase of the life expectancy that is seen today in the entire planet, a larger number of individuals reaches an advanced age when the manifestation of neurodegenerative illnesses is more frequent. Among these, the Alzheimer's disease (AD) is the most common cause of dementia. The most substantial findings in the brains of patients suffering from AD are the senile plaques, the neurofibrillary tangles and an extensive neuronal loss. However, a general deficiency of predictive biological markers for AD impairs the correct diagnosis and the better understanding of the disease. Studies of molecular genetics allowed the identification of four genes that are consistently linked to AD: APP, apoE, PSEN1 and PSEN2. However, diverse studies demonstrate that other genes also play important roles in the development of AD, strengthening the notion that it is a polygenic illness. Modern large-scale techniques can now be applied in the study of AD, permitting the study of a vast population of genes or molecular alterations that can explain the origin of the illness, offering the basis for the understanding of the pathogenesis of AD and enabling the delineation of new and more efficient approaches to treat and to prevent the sprouting of the disease.Com o aumento da expectativa de vida, visto hoje em todo o planeta, um maior número de indivíduos alcança uma idade avançada em que a manifestação de doenças neurodegenerativas é mais freqüente. Entre essas, a doença de Alzheimer (DA) é a causa mais freqüente de demência. Os achados mais marcantes na DA, em cérebros de pacientes acometidos pela doença, são as placas senis, os emaranhados neurofibrilares e a extensa perda neuronal. No entanto, existe uma carência generalizada de marcadores biológicos preditivos ou com valor diagnóstico para a DA. Estudos de genética molecular permitiram identificar quatro genes consistentemente associados com o maior risco de desenvolvimento da doença: APP, apoE, PSEN1 e PSEN2. No entanto, inúmeros estudos apontam para papel importante de outros genes, fortalecendo a hipótese de uma doença poligênica e multifatorial. Neste sentido, novas abordagens de estudo têm um futuro promissor, podendo indicar uma vasta população de genes ou alterações moleculares que possam explicar o surgimento da doença, vindo a fornecer as bases para a compreensão da DA e também para o delineamento de novas e mais eficazes abordagens de tratamento ou prevenção da doença

Detecting ovarian cancer using extracellular vesicles: Progress and possibilities

Ovarian cancer (OC) is the deadliest gynecological malignancy. Most patients are diagnosed when they are already in the later stages of the disease. Earlier detection of OC dramatically improves the overall survival, but this is rarely achieved as there is a lack of clinically implemented biomarkers of early disease. Extracellular vesicles (EVs) are small cell-derived vesicles that have been extensively studied in recent years. They contribute to various aspects of cancer pathology, including tumour growth, angiogenesis and metastasis. EVs are released from all cell types and the macromolecular cargo they carry reflects the content of the cells from which they were derived. Cancer cells release EVs with altered cargo into biofluids, and so they represent an excellent potential source of novel biomarkers for the disease. In this review we describe the latest developments in EVs as potential biomarkers for earlier detection of OC. The field is still relatively young, but a number of studies have shown that EVs and the cargo they carry, including miRNAs and proteins, can be used to detect OC. They could also give insight into the stage of the disease and predict the likely therapeutic outcome. There remain a number of challenges to the use of EVs as biomarkers, but through ongoing research and innovation in this exciting field there is great potential for the development of diagnostic assays in the clinic that could improve patient outcome

Next-Generation Phage Display: Integrating and Comparing Available Molecular Tools to Enable Cost-Effective High-Throughput Analysis

Background: Combinatorial phage display has been used in the last 20 years in the identification of protein-ligands and protein-protein interactions, uncovering relevant molecular recognition events. Rate-limiting steps of combinatorial phage display library selection are (i) the counting of transducing units and (ii) the sequencing of the encoded displayed ligands. Here, we adapted emerging genomic technologies to minimize such challenges. Methodology/Principal Findings: We gained efficiency by applying in tandem real-time PCR for rapid quantification to enable bacteria-free phage display library screening, and added phage DNA next-generation sequencing for large-scale ligand analysis, reporting a fully integrated set of high-throughput quantitative and analytical tools. The approach is far less labor-intensive and allows rigorous quantification; for medical applications, including selections in patients, it also represents an advance for quantitative distribution analysis and ligand identification of hundreds of thousands of targeted particles from patient-derived biopsy or autopsy in a longer timeframe post library administration. Additional advantages over current methods include increased sensitivity, less variability, enhanced linearity, scalability, and accuracy at much lower cost. Sequences obtained by qPhage plus pyrosequencing were similar to a dataset produced from conventional Sanger-sequenced transducing-units (TU), with no biases due to GC content, codon usage, and amino acid or peptide frequency. These tools allow phage display selection and ligand analysis at.1,000-fold faster rate, and reduce costs,250fol

Identical sequence patterns in the ends of exons and introns of human protein-coding genes

Intron splicing is one of the most important steps involved in the maturation process of a pre-mRNA. Although the sequence profiles around the splice sites have been studied extensively, the levels of sequence identity between the exonic sequences preceding the donor sites and the intronic sequences preceding the acceptor sites has not been examined as thoroughly. In this study we investigated identity patterns between the last 15 nucleotides of the exonic sequence preceding the 5' splice site and the intronic sequence preceding the 3' splice site in a set of human protein-coding genes that do not exhibit intron retention. We found that almost 60% of consecutive exons and introns in human protein-coding genes share at least two identical nucleotides at their 3' ends and, on average, the sequence identity length is 2.47 nucleotides. Based on our findings we conclude that the 3' ends of exons and introns tend to have longer identical sequences within a gene than when being taken from different genes. Our results hold even if the pairs are non-consecutive in the transcription order. (C) 2012 Elsevier Ltd. All rights reserved.CNPq [382791/2009-6]CNPqMCT/CT-SaudeMCT/CTSaudeDECIT/SCTIE/MSDECIT/SCTIE/MS [577593/2008-0, 312733/2009-7]Swiss Bridge FoundationSwiss Bridge FoundationFundacao do CancerFundacao do CancerINCA/MSINCA/MSAssociacao Beneficente Alzira Denise Hertzog Silva (ABADHS)Associacao Beneficente Alzira Denise Hertzog Silva (ABADHS