Glycation vs. glycosylation: a tale of two different chemistries and biology in Alzheimer’s disease

Abstract

In our previous studies, we reported that the activity of an anti-oxidant enzyme, Cu,Zn-superoxide dismutase (Cu,Zn-SOD) became decreased as the result of glycation in vitro and in vivo. Glycated Cu,Zn-SOD produces hydroxyl radicals in the presence of transition metals due to the formation of a Schiff base adduct and a subsequent Amadori product. This results in the site-specific cleavage of the molecule, followed by random fragmentation. The glycation of other anti-oxidant enzymes such as glutathione peroxidase and thioredoxin reductase results in a loss or decrease in enzyme activity under pathological conditions, resulting in oxidative stress. The inactivation of anti-oxidant enzymes induces oxidative stress in aging, diabetes and neurodegenerative disorders. It is well known that the levels of Amadori products and N(e)-(carboxylmethyl)lysine (CML) and other carbonyl compounds are increased in diabetes, a situation that will be discussed by the other authors in this special issue. We and others, reported that the glycation products accumulate in the brains of patients with Alzheimer's disease (AD) patients as well as in cerebrospinal fluid (CSF), suggesting that glycation plays a pivotal role in the development of AD. We also showed that enzymatic glycosylation is implicated in the pathogenesis of AD and that oxidative stress is also important in this process. Specific types of glycosylation reactions were found to be up- or downregulated in AD patients, and key AD-related molecules including the amyloid-precursor protein (APP), tau, and APP-cleaving enzymes were shown to be functionally modified as the result of glycosylation. These results suggest that glycation as well as glycosylation are involved in oxidative stress that is associated with aging, diabetes and neurodegenerative diseases such as AD.

<p>High-fat diet-induced kidney alterations in rats with metabolic syndrome: endothelial dysfunction and decreased antioxidant defense</p>

“…[16][17][18] AGE/ALE are irreversible products expressed ubiquitously and overproduced in pathologies such as diabetes, CKD, Alzheimer disease, and non-alcoholic fatty liver disease. [19][20][21][22] Additionally, PM has anti-inflammatory, antioxidant, and metabolic effects, which makes it a promising candidate for the management of MetS related renal alterations. 23 However, the effect of PM on renal endothelial dysfunction due to high-fat diet (HFD)-induced MetS remains unveiled.…”

Metabolic Derangements Contribute to Reduced sRAGE Isoforms in Subjects with Alzheimer’s Disease

“…RAGE has a diverse set of ligands, which include advanced glycation end products (AGEs), beta-amyloid (A β ), and members of the S100/calgranulin protein family [ 12 , 13 ]. These ligands and the RAGE protein are increased in the postmortem brains of AD patients, and interactions between RAGE and its ligands are related to the pathophysiology of chronic disease [ 14 , 15 ]. More specifically, it has been documented that in the AD brain, there is an overexpression of glial-derived factors including the S100B protein [ 16 ].…”

Early Stage Glycosylation Biomarkers in Alzheimer’s Disease

“…However there is no site specific addition of O-glycans to serine or threonine residues and the core structure of an O-glycan is variable, therefore O-glycan synthesis is not always initiated by the same glycosyltransferase [58]. The focus of this review is on N-glycans which are present in 90% of glycoproteins [59], are the most characterised of all glycans and strongly implicated in the AD pathogenesis [60,61,62,63,64]. A single enzyme known as oligosaccharyltransferase initiates glycan synthesis in the N-linked pathway.…”