SASAKI Nobuyuki Sapporo Medical University, School of Medicine, Department of Neuropsychiatry, Assistant, 医学部, 助手 (60315497)
KIKUCHI Seiji Hokkaido University School of Medicine, Department of Neurology, Assistant Professor, 大学院・医学研究科, 講師 (10271660)
|Budget Amount *help
¥13,700,000 (Direct Cost: ¥13,700,000)
Fiscal Year 2002: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 2001: ¥8,700,000 (Direct Cost: ¥8,700,000)
The Maillard reaction that leads to the formation of advanced glycation end-products (AGEs) plays an important role in the pathogenesis of angiopathy in diabetic patients, in aging and in neurodegenerative processes.
1) We developed anti-AGE antibodies that specifically recognize six distinct classes of AGE structures (AGE-1, glucose-derived AGEs, AGE-2, glyceraldehydes-derived AGEs ; AGE-3, glycolaldehyde-derived AGEs ; AGE-4, methylglyoxal- derived AGEs ; AGE-5, glyoxal-derived AGEs ; and AGE-6, 3-deoxyglucosone-derived AGEs) within the circulating proteins and peptides present in serum from diabetic patients on hemodialysis.
2) We recently reported that an elevation of serum AGE levels was found to be associated with severity of diabetic retinopathy. We also reported that AGEs in the serum of diabetic patients on hemodialysis have diverse biological activities on vascular wall, kidney mesangial and cortical neuronal cells. Therefore, these results suggest a causal role for these types
of AGEs in the pathogenesis of diabetic complication and neurodegenerative disease.
3) Incubation of cortical neurons with six immunochemically distinct AGEs, designated AGEs-1 to -6, produced a dose-dependent increase in neuronal cell-death. The structural epitope designated AGE-2 (glyceraldehyde-derived AGEs) was found to have the greatest cytopathic effect and the neurotoxicity of AGE-2 was neutralized by the addition of an anti-AGE-2 specific antibody. We provide the first evidence for the toxicity of a specific AGE structure, defined as AGE-2, on rat primary cultured cortical neuronal cells.
4) The immunohistochemical study showed that AGE-2 existed in the Alzheimer's brain. The AGE-2 was mainly localized in the cytosol of neurons, not in the nucleus, astrocytes, and extracellular area. Senile plaques were not stained with the anti-AGE-2 antibody. There was no difference in neurotoxicity between AGE-2-Aβ and Aβ only. These results suggested that AGE-2 promotes neurotoxicity without reference to Aβ. We hypothesized that the AGE-2 immunopositive reaction in the pericaryon reflects the increase generation of AGE-2 in cytoplasm that occurs with the decline of GAPDH.
5) Recently, it has become clear that AGEs also have a role in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, and amyotrophic lateral sclerosis (ALS). Less