Role of Glycation in Mild Cognitive Impairment Contributing to Pathophysiology of Alzheimer’s Disease

Abstract

Mild cognitive impairment (MCI) is the transition state between normal cognition and dementia. The prevalence of MCI is estimated to be about 15-20% in individuals aged 60 and above. Individuals with MCI bear a higher risk of transitioning towards Alzheimer’s disease (AD). Glycation, a spontaneous post transitional modification, has been implicated to be involved in MCI and through interaction with receptor for advanced glycation end products (RAGE) modulates progression to AD through initiating neuroinflammation and oxidative stress. Glyoxalase 1 and 2 (GLO1 and 2) serve as the major antioxidant system through which AGEs are detoxified. The present study aimed to investigate the role of glycation in MCI through determining the expression of GLO1, GLO2 and RAGE as well and construction of a knowledge driven biological pathway to predict the underlying mechanisms of glycation in MCI that can potentially lead to AD. Human blood samples (n = 116) were collected from a major local hospital at Rawalpindi with MoCA scores < 26 and age group above 50. Demographic analysis of the disease group revealed mean age of 61.76 in males while for females it was 54.48 (p value < 0.0001). The mean MoCA score was 19.39 for males and 17.98 for females in the MCI group (p value = 0.0038). The patients displayed varied levels of physical activity for both sexes as well as presence of comorbidities. Expressions of GLO1, GLO2 and RAGE were determined through quantitative polymerase chain reaction (qPCR) and while GLO1 and GLO2 exhibited a significant decrease in expression in disease group (p value <0.001), RAGE showed variations in expression level based on presence of comorbidities. Individuals with diabetes and hypertension exhibited significantly increased RAGE expression while individuals who did not present any comorbidity exhibited decreased RAGE levels (p value < 0.0001).Insilico analysis using various computational tools, including PubMed, Kyoto Encyclopedia of Genes and Genomes (KEGG), wiki pathways, STRING pathway and gene MANIA revealed that RAGE interacts with advanced glycation end products (AGEs) and amyloid ꞵ (Aβ) to activate numerous signal transduction pathways through its interacting partner diaphanous 1 (DIAPH1). These include NADPH oxidase (NOX) dependent, extracellular regulated kinase (ERK), p38 mitogen-activated protein kinases (p38 MAPK), Phosphoinositide 3-kinases (PI3K) pathways that induce reactive oxygen species (ROS) and nuclear factor kappa-light-chain-enhancer of activated B cells (NfkB) promoting neuroinflammation and neurodegeneration that also leads to inhibition of GLO1 and GLO2. In conclusion, this preliminary data highlights the potential involvement of glycation in MCI and AD. These findings further stipulate the neuroinflammatory role of RAGE and its interacting partners and can be considered as targets for future diagnostic and therapeutic interventions.