Effects of DNA methylation and demethylation on LRP1 and RAGE genes as crucial factors in Alzheimer's disease pathophysiology

Abstract

Presently there is a growing number of scientific papers that indicate a strong connection between epigenetics and the Alzheimer's disease (AD) pathophysiology. This study also concentrates on some events related to this serious, chronic, and lethal neurodegenerative disease. Actually, this disease, with a still incomplete knowledge of its etiology and closely connected to the ageing process and old age, in conditions of intensive ageing of the world population (so called senectual explosion), is increasingly becoming a burden for contemporary society. The most recent scientific papers related to AD pathophysiology indicate the complex interaction of a number of genes and oxidative and glycative stress, as well as epigenetic phenomena. The two mentioned types of stress have been under intensive research for a longer period of time; however, epigenetics is a new challenging field that penetrates into the essence of this disease with promising results. Epigenetics, as opposed to genetics that is concerned with gene mutations, investigates special events that are not directly connected to genes, but events that affect genes not changing their sequential structure. This study does not analyze histone acetylation (adding the acetyl group CH₃CO- to histones) and deacetylation, nor histone methylation (adding the methyl group - CH₃ to histones) and demethylation; it is primarily concerned with DNA methylation as the crucial epigenetic event essential for the process of the transcription of genes and their adequate expression. Special emphasis is directed to the analysis of the low- density lipoprotein receptor-related protein (LRP1) receptor, the extremely important factor in the amyloid beta (Aβ) drainage from the brain, and to the decline of the LRP1 expression on the membrane abluminal side of the blood brain barrier (BBB) endothelial cells. This paper does not analyze oxidative and glycative damage of the LRP1 receptor, and it does not focus on AD therapy; it is primarily concerned with epigenetics.