Status of DNA base excision repair in brain from individuals with Alzheimer's Disease

• Grant number: 12/11889-6
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: September 01, 2012
• End date: November 30, 2015
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Nadja Cristhina de Souza Pinto
• Grantee: Daniela Tathiana Soltys
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated scholarship(s): 15/03148-4 - Quantification and identification of mitochondrial DNA mutations in brains from individuals with Alzheimer's Disease, BE.EP.PD

Abstract

The population aging observed in the last century has led to a significant increase in the number of cases of Alzheimer's disease (AD) in the world, whose associated costs are becoming significant to the public health systems. Despite major recent advances in identifying genes and cellular targets involved in the pathophysiology of the disease, the molecular mechanisms that lead to the functional and histological changes observed in patients with AD have not been fully elucidated yet. Recent studies suggest that the accumulation of oxidative modifications in DNA caused by exposure to reactive oxygen species, and changes in the pathways that remove these lesions may have a role in the progression of AD. These lesions are primarily removed by the DNA repair pathway known as Base Excision Repair (BER). In an earlier study, our group demonstrated that BER activities are lower in brains from AD patients than in brains from age-matched normal subjects. These results lead to the hypothesis that lower BER sensitizes neurons to cell death induced by amyloid plaques and neurofibrilary tangles. Here, we propose to test this hypothesis by measuring BER in brains from individuals who have neuropathological changes of AD, but remained cognitively normal due to the development of a greater cognitive reserve. The main objective of this study is to determine whether alterations in BER activities are involved in the development of AD and in the loss of the cognitive reserve. The information that the activity of BER may act as a modulator of cognitive reserve, and therefore of the clinical outcome in AD, may contribute to both the clinical management of these patients and to identify risk groups. We also expected to contribute for the better understanding of the role of oxidative DNA damage to the sequence of molecular events leading to neuronal death associated with the progress of AD. (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)

MORI, MATEUS P.; COSTA, RUTE A. P.; SOLTYS, DANIELA T.; FREIRE, THIAGO DE S.; ROSSATO, FRANCO A.; AMIGO, IGNACIO; KOWALTOWSKI, ALICIA J.; VERCESI, ANBAL E.; DE SOUZA-PINTO, NADJA C.. Lack of XPC leads to a shift between respiratory complexes I and II but sensitizes cells to mitochondrial stress. SCIENTIFIC REPORTS, v. 7, MAR 13 2017. (12/11889-6, 08/57952-5, 10/51906-1, 11/50400-0, 08/57721-3, 06/59786-0, 13/07937-8)