Evaluation of the efficiency of DNA repair mechanisms and gene expression in lymphocytes from patients with Alzheimer's Disease

• Grant number: 12/07879-5
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: July 01, 2012
• End date: February 13, 2016
• Field of knowledge: Biological Sciences - Genetics - Mutagenesis
• Principal Investigator: Elza Tiemi Sakamoto Hojo
• Grantee: Giovana da Silva Leandro
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated scholarship(s): 13/11052-1 - Influence of DNA repair deficiency in the development and progression of Alzheimer's Disease in mouse model, BE.EP.DR

Abstract

The genome of organisms is exposed to endogenous and exogenous agents, which can induce DNA damage and alter the integrity of DNA, generating genomic instability. Oxidative stress, one of the processes that can generate genomic instability in cells, is a condition resulting from lack of balance between the generation of free radicals and the effectiveness of antioxidant defense mechanisms. According to literature, the oxidative stress is associated with aging as well as in the pathogenesis of neurodegenerative diseases like Alzheimer's disease (AD). This is a chronic neurodegenerative dementia with great impact on public health, whose development seems to be associated with oxidative stress as well as the failures in the mechanisms of DNA repair. Despite the research to identify risk factors to AD, studies on the molecular basis of this have been inconclusive, with the expectation that they may provide important information for the understanding of AD and new possibilities for viable strategies in clinical practice. This project aims to evaluate the response to oxidative stress and the efficiency of DNA repair in lymphocytes of patients with AD (compared to elderly and young individuals) based on the hypothesis that oxidative damage is implicated in the aging process and the development of AD and the peripheral blood lymphocytes may have molecular changes due to the disease. For this, samples of peripheral blood will be collected from individuals with AD, healthy individuals (similar age) and young subjects, fitted the inclusion criteria. The lymphocytes will be processed according to the type of assay. Analysis of gene expression will be carried out mainly for classes of genes playing role in oxidative damage responses and DNA repair. For some genes, we will perform studies on protein expression by Western blot. Lymphocyte cultures will be submitted to in vitro treatment with potassium bromide (a positive control), to analyze DNA damage by the comet assay; this procedure allows quantification of DNA breakage; in parallel, cell cycle progression and apoptosis rates will be analyzed by flow cytometry. We will also study the transcript expression of genes related to TP53 pathway, since TP53 was differentially modulated in patients with AD (data obtained previously), as well as micro-RNAs related to this pathway. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

LEANDRO, GIOVANA SILVA; EVANGELISTA, ADRIANE FEIJO; LOBO, ROMULO REBOUCAS; XAVIER, DANILO JORDAO; MORIGUTI, JULIO CESAR; SAKAMOTO-HOJO, ELZA TIEMI. Changes in Expression Profiles Revealed by Transcriptomic Analysis in Peripheral Blood Mononuclear Cells of Alzheimer's Disease Patients. JOURNAL OF ALZHEIMER'S DISEASE, v. 66, n. 4, p. 1483-1495, 2018. (12/07879-5, 13/09352-7)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

LEANDRO, Giovana da Silva. Gene expression alterations in peripheral blood mononuclear cells of Alzheimer\'s disease patients and consequences of polymerase β deficiency in mouse fibroblasts. 2016. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) Ribeirão Preto.