Functional, epigenetic and genetic aspects of base excision repair pathway in Alzheimer's disease

Neurodegenerative diseases are a growing problem in the modern world. A significant pool of neurodegenerative diseases are age-related dementia diseases (as Alzheimer's disease). Development of effective therapies effective in treating Alzheimer's disease is hindered by its complex nature, and by unsatisfactory level of understanding its pathophysiology at the molecular level. Although the pathogenesis of Alzheimer's disease, remains elusive, the results of the studies show the complexity of this disease, which consists of age, and genetic and environmental factors. Due to the still little knowledge of the genetic basis of Alzheimer's disease is reasonable to searching genes that may have a close relationship with the occurrence of such disease. In addition, it is known that increased oxidative DNA damage, as well as mutations and deletions in genes encoding antioxidant and DNA repair proteins may be associated with the development of neurodegenerative diseases (including Alzheimer's disease). Moreover base excision repair (BER) is the major pathway for repairing DNA base modifications caused by oxidation and there is indication that the brain in Alzheimer's disease is subjected to both increased oxidative DNA damage and decreased BER activity. Additionally, previous results indicate on complexity of the mechanisms leading to neurodegeneration.

As the post-mortem examination in the human cells of the central nervous system (CNS) obtained from a large number of dead Alzheimer's patients are almost impossible to perform (impossible to obtain of such material in large number in Poland) and the fact that we cannot extrapolate the results obtained in studies of peripheral blood leukocytes (material in this research project) to the cells of the CNS, which directly affect the neurodegeneration, we are going to investigate the molecular mechanism associated neurodegenerative changes in Alzheimer's disease. The mechanisms associated with neurodegeneration might be very important in understanding a complex, still unclear, molecular basis of neurodegeneration in human cells.

Aim of the study. Proposed studies aim to determine molecular mechanism associated neurodegenerative changes in Alzheimer's disease based on BER system. This aim will be achieved by examining the accumulation of oxidative DNA damage in patients with Alzheimer's disease and clarify whether it is caused by increased formation of this type of damage, or by reduced level of BER, a primary system for removing and repairing such damage. Also we are going to identify associated neurodegeneration molecular markers (genetic, epigenetic or functional) necessary for an early identification and differentiation, and prognosis of Alzheimer's disease. It is expected that these studies should allow for a better understanding of the molecular complexity of Alzheimer's disease. Investigation of the associated mechanisms of genetic, epigenetic, and functional aspects of BER which may be related to the development and progression of this disease may allow for early identification of associated neurodegenerative changes in the patient’s cells, a better prognosis of disease, and in the future on the development of targeted therapy (pharmacological, genetic or cellular) of Alzheimer's disease.