Análisis de asociación genética para el estudio de la patogénesis de la enfermedad de Alzheimer

Abstract

Sporadic Alzheimer’s Disease (AD) is a multifactorial trait of elderly resulting from combinations of genes and environmental factors. Neither environmental nor genetic factors causes the disease, but both are necessary but not sufficient for the development of the disease. Our aim is to find novel genes modulating AD risk and/or important in the pathogenesis processes underlying the disease, which constitute potential therapeutic targets. Previously at our laboratory, we have analyzed gene expression of neuronal cell models mimicking several aspects of AD pathogenesis and we have selected the most responder genes or altered functions. Polymorphisms at these genes are analyzed by association studies in case - control samples, which are a valuable tool for identifying genes contributing to the disease. If the pathogenesis process mimicked in the model is actually involved in the pathogenesis, allelic variants could modulate susceptibility to AD. The models developed at the laboratory mimicks APP-overexpression, adrenergic, oxidative, endoplasmic reticulum stress and convergence of oxidative and endoplasmic reticulum stress simultaneously (this condition generates the Integrated Stress Response, ISR). In addition, we have studied related human genes with the infection by Herpes Simplex Virus type I (HSV-1). By this strategy, we have identified several genes among the most regulated in the human neuroblastoma SK-N-MC as a response to the stresses, that are associated with AD, supporting the hypothesis that the mentioned processes are really involved in the pathogenesis of the disease. Also, all the HSV-1-related genes studied shown association with AD, suggesting that infection by this virus may be an important AD pathogenic process. In addition, we have carried out the functional analysis of a biallelic polymorphism located in the promoter region of DDIT3, a gene that stimulates with ISR to conduct cells to apoptosis. We have observed that the promoter response to oxidative and endoplasmic reticulum stress differs from one allele to the other one, suggesting that allelic variants altering neuron responsiveness to stress could be important to modulate susceptibility to AD. This observation was also supported by the finding that thi s polymorphism modulates the risk and the age of onset of Alzheimer’s disease.