Behavioral and Proteomic Studies Reveal Methylglyoxal Activate Pathways Associated with Alzheimer’s Disease

Abstract

Diabetes is one of the major risk factors for Alzheimer’s disease (AD) development. The role of elevated levels of glucose, methylglyoxal (MGO), and advanced glycation end products (AGEs) in the pathogenesis of AD is not well understood. In this pursuit, we studied the role of methylglyoxal in the pathogenesis of AD in rat models. The elevated plus-maze (EPM) behavioral study indicated that MGO induces anxiety. Treatment of telmisartan (RAGE expression inhibitor) and aminoguanidine (MGO quencher) attenuated MGO induced anxiety. Further, hippocampal proteomics demonstrated that MGO treated rats differentially regulate proteins involved in calcium homeostasis, mitochondrial functioning, and apoptosis, which may affect neurotransmission and neuronal plasticity. The hippocampal tau phosphorylation level was increased in MGO treated rats, which was reduced in the presence of aminoguanidine and telmisartan. The plasma fructosamine level was increased upon MGO treatment. Hippocampal histochemistry showed vascular degeneration and neuronal loss upon MGO treatment. This study provides mechanistic insight into the role of MGO in the diabetes-associated development of AD.

RAGE Inhibitors in Neurodegenerative Diseases

“…The AGE–RAGE interactions and binding of RAGE with various other ligands not only contributes to the exacerbation of oxidative stress but also to the over-expression of RAGEs themselves. The signaling pathways arising from AGE–RAGE interactions are implicated in a variety of pathological disorders, including neurodegeneration, cardiovascular diseases, cancer, diabetic neuropathy, diabetic retinopathy and diabetes [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 50 ]. Furthermore, in Parkinson’s Disease (PD) cases, microglial cell-mediated neuroinflammation and α-synuclein aggregation are exacerbated upon the binding of RAGE to receptors on α-synuclein fibrils on microglia [ 34 ].…”

“…Although pathogenesis due to AGEs is multifactorial, recently it has been recognized that a key factor in the pathogenesis of AGEs is through their binding to receptors for Advanced Glycation Endproducts (RAGE), which results in a deleterious activation of a cascade of signaling events, and the formation of pro-inflammatory cytokines that triggers further oxidative stress and an excessive build-up of AGEs and RAGE. That is, the higher concentration of AGEs would lead to the increased expression of RAGE and this vicious cycle leads to the onset of neurodegenerative diseases, including AD, ALS, progression of the secondary effects of TBI, diabetes, atherosclerosis, rheumatoid arthritis, and cancers [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. Other endogenous ligands, including high mobility group box1 (MGB1) proteins, also contribute to the RAGE-induced inflammatory responses (through intracellular signaling activation of the TLR4/NF-κB/interleukin pathway), as demonstrated in the TBI animal models [ 15 ].…”

Application of Proteomics in Alzheimer’s Disease: A Mini Review

“…Since the aetiology of AD is multifactorial, other animal models with other symptoms, such as anxiety, depression (103) and diabetes related to AD (104) have also been studied. Triple transgenic mice of AD (3xTg-AD) treated with melatonin have been evaluated via open field test, elevated plus maze test, forced swimming test, and tail suspension test.…”

“…The researchers discovered that glutathione S-transferase P 1 (GSTP1) (an anxiety-associated protein) and complexin-1 (CPLX1) (a depression-associated protein) which related to AD were significantly down-regulated in the hippocampus of 3xTg-AD mice (103). The role of methylglyoxal (MGO) in the pathogenesis of AD in a rat model has also been evaluated via behavioural and proteomic studies (104). MGO is a toxic by-product of glycolysis which is high in diabetes patients.…”