Involvement of Advanced Glycation End-products (AGEs) in Alzheimers Disease

Masayoshi      Takeuchi; Seiji      Kikuchi; Nobuyuki      Sasaki; Takako      Suzuki; Takayuki      Watai; Mina      Iwaki; Richard      Bucala; Sho-ichi      Yamagishi

Abstract

The advanced stage of the glycation process (one of the post-translational modifications of proteins) leads to the formation of advanced glycation end-products (AGEs) and plays an important role in the pathogenesis of angiopathy in diabetic patients. It has recently become clear that AGEs also influence physiological aging and neurodegenerative diseases such as Alzheimers disease (AD) and amyotrophic lateral sclerosis (ALS). Recently we have provided direct immunochemical evidence for the existence of six distinct AGE structures within the AGE-modified proteins and peptides that circulate in the serum of diabetic patients on hemodialysis (DM-HD). We showed a direct toxic effect of the synthetic AGE-2 (glyceraldehyde-derived AGEs) on cortical neuronal cells and provided evidence for a toxic effect of AGE-2 present in DM-HD serum. These results indicate that of the various types of AGE structures that can form in vivo, the AGE-2 structure is likely to play an important role in the pathophysiological processes associated with AGE formation. In AD brains, AGE-2 epitope was mainly present in the cytosol of neurons in the hippocampus and para-hipocampal gyrus. Protein cross-linking by AGE structures results in the formation of protease-resistant aggregates. Such protein aggregates may interfere with both axonal transport and intracellular protein traffic in neuron. In this review, we provide an outline of AGEs formation in vivo and propose that the novel structural epitope AGE-2 is an important toxic moiety for neuronal cells in AD.

Keywords: advanced glycation end-products (AGEs), glyceraldehyde-derived AGEs, AGE-2 structure, Alzheimers disease (AD), diabetes mellitus (DM), neurotoxicity, apoptosis, glyceraldehyde-3-phosphate dehydrogenase (GAPDH)