Study on rage amyloid interaction with relevance to alzheimer s disease pathology and influence of g82s rage polymorphism on the above interaction

Abstract

Alzheimer s disease (AD) is one of the most common neurodegenerative diseases in the elderly and is characterized by the accumulation of amyloid beta (Aand#946;) protein in the form of plaques and neurofibrillary tangles, which contains tau proteins. Receptor for Advanced Glycation End products (RAGE) is a protein belonging to the immunoglobulin superfamily, which functions as a receptor for various types of ligands like AGEs (Advanced Glycation End products), members of S100 / calgranulin family, and high mobility group box-1 (HMGB1). It also acts as a receptor for Aand#946; proteins and upon binding, triggers various stress-related inflammatory pathways. However certain splice variants of RAGE like endogenous secretory RAGE (esRAGE) and soluble RAGE (sRAGE) competes with fRAGE for Aand#946; binding thereby acting as decoy receptors for amyloid beta and improves the clearance of Aand#946;. While thirty different polymorphisms were reported in the RAGE gene, G82S polymorphism was shown to be associated with AD. The study was aimed to investigate the G82S RAGE polymorphism with AD in the South Indian population and also to study the mechanism of its association. newlineWith this major objective, the clinical study is designed to analyze the frequency of G82S RAGE polymorphism and characterization of RAGE splice variants in peripheral blood mononuclear cells (PBMC) and plasma of the AD patients and age-matched healthy controls. sRAGE and total RAGE expression were quantified and correlated with plasma amyloid load. The influence of G82S RAGE polymorphism on the plasma levels of sRAGE and Aand#946;42 was also assessed. The prevalence of polymorphisms was estimated using the conventional PCR-RFLP method and quantification of various RAGE splice variants was performed using RT-qPCR. While homozygous mutant genotype of SS was not observed in the study population, heterozygous genotype (GS) was distributed more in AD compared to control and it is statistically newlinesignificant. Plasma Aand#946;42 was significantly elevated whereas the sRAGE was decreased in AD compared t