Sugared proteins, unsweet outcomes : Glycation, RAGE signaling, and their relation to diabetes and Alzheimer’s Disease

Protein glycation is a non-enzymatic reaction between reducing sugars and amino groups in proteins, resulting in the formation of advanced glycation end-products (AGEs). These modifications accumulate during aging and are accelerated under hyperglycemic conditions such as type 2 diabetes. Although the chemistry of glycation and the Maillard reaction is well characterized, the biological consequences of distinct glycation chemistries remain incompletely understood. In particular, it is unclear how dietary and endogenous glycation products engage AGE receptors, drive inflammation, and influence disease-related protein interactions. This thesis aimed to elucidate how protein glycation affects structure, receptor binding, immune activation, and functional outcomes in both nutritional and pathological contexts. Dietary glycation was investigated using soy proteins heated with glucose as a controlled Maillard reaction model. Progression of glycation chemistry closely tracked biological activity. Early-stage reaction products already showed measurable binding to AGE receptors, including the receptor for advanced glycation end-products (RAGE), galectin-3, and scavenger receptors. Prolonged heating increased aggregation, receptor affinity, and low-grade inflammatory responses in monocytes and macrophages, characterized by enhanced secretion of IL-1beta, IL-8, and TNFalpha. These findings demonstrate that dietary Maillard products are biologically active and that heating duration is a key predictor of immunogenicity. Endogenous glycation was examined using human serum albumin (HSA), a highly abundant and glycation-prone plasma protein. Glycation induced by methylglyoxal (MGO) caused greater structural disruption and stronger receptor engagement than glucose-mediated glycation. MGO-glycated HSA elicited pronounced inflammatory responses in macrophages, whereas carboxymethyl-lysine (CML)-modified HSA was the strongest activator in primary human monocytes. These results highlight the pro-inflammatory potential of both dicarbonyl stress and CML formation, with RAGE emerging as a central signaling hub. The impact of glycation on HSA’s interaction with amyloid-beta (Abeta) peptides was examined to explore potential links between metabolic disease and neuroinflammation. Native HSA reduced Abeta-induced inflammation and aggregation, whereas glucose-glycated HSA lost this protective capacity and accelerated Abeta fibrillization. Glycated HSA readily formed complexes with Abeta that exhibited enhanced RAGE binding and provoked stronger inflammatory responses than complexes with non-glycated HSA, identifying these complexes as highly bioactive ligands at the metabolic–cognitive interface. Finally, the role of AGE receptors in phagocytosis was investigated. Direct RAGE engagement was sufficient to promote uptake in macrophages; however, glycation chemistry modulated effective clearance. Glucose- and CML-modified proteins impaired phagocytosis compared to native protein, whereas MGO-modified proteins preserved uptake capacity, suggesting that certain AGE structures may interfere with inflammatory resolution. Together, these findings demonstrate that glycation chemistry and molecular presentation, rather than protein origin alone, determine biological activity. They underscore the importance of dietary processing control, mitigation of dicarbonyl stress, and modulation of RAGE signaling as strategies to limit glycation-driven inflammation and its contribution to metabolic and neurodegenerative disease.