TAGE (toxic AGEs) hypothesis in various chronic diseases

Area of Science:

• Biochemistry
• Pathophysiology
• Molecular Biology

Background:

• Advanced glycation end-products (AGEs) are post-translational modifications implicated in diabetic angiopathy, aging, and neurodegenerative diseases.
• The specific AGEs subtypes and their receptors involved in pathogenesis remain unclear.
• Previous research has identified six distinct AGEs structures circulating in diabetic patients' serum.

Purpose of the Study:

• To investigate the pathogenetic roles of distinct AGEs subtypes.
• To identify which AGEs receptor mediates AGEs effects on cells.
• To differentiate between toxic and non-toxic AGEs structures in disease processes.

Main Methods:

• Direct immunochemical evidence was used to identify six distinct AGEs structures (AGEs-1 to -6).
• The biological activities of glyceraldehyde-derived AGEs (AGEs-2) and glycolaldehyde-derived AGEs (AGE-3) were assessed on various cell types.
• Cytotoxic activity of acetaldehyde (AA)-derived AGEs (AA-AGE) on cortical neurons was evaluated, and AA-AGE epitopes were detected in human brain tissue.

Main Results:

• Six distinct AGEs structures were identified in the serum of diabetic patients.
• AGEs-2 and AGEs-3 demonstrated diverse biological activities on vascular cells, mesangial cells, Schwann cells, melanoma cells, and cortical neurons.
• AA-AGE exhibited cytotoxic effects on cortical neurons and was found in the brains of alcoholics.

Conclusions:

• Toxic AGEs (TAGE) structures, specifically AGEs-2, AGEs-3, and AA-AGE, are likely significant contributors to the pathophysiology of AGEs-related diseases.
• Non-toxic AGEs, such as N-carboxymethyllysine, pentosidine, and pyrraline, do not appear to play a major role.
• This research clarifies the role of specific AGEs subtypes in disease.