Induction of neuronal death by microglial AGE-albumin: implications for Alzheimer's disease.
Advanced glycation end products (AGEs) have long been considered as potent molecules promoting neuronal cell death and contributing to neurodegenerative disorders such as Alzheimer's disease (AD). In this study, we demonstrate that AGE-albumin, the most abundant AGE product in human AD brains, is synthesized in activated microglial cells and secreted into the extracellular space. The rate of AGE-albumin synthesis in human microglial cells is markedly increased by amyloid-β exposure and oxidative stress. Exogenous AGE-albumin upregulates the receptor protein for AGE (RAGE) and augments calcium influx, leading to apoptosis of human primary neurons. In animal experiments, soluble RAGE (sRAGE), pyridoxamine or ALT-711 prevented Aβ-induced neuronal death in rat brains. Collectively, these results provide evidence for a new mechanism by which microglial cells promote death of neuronal cells through synthesis and secretion of AGE-albumin, thereby likely contributing to neurodegenerative diseases such as AD.
Center for Genomics and Proteomics, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, Korea.
Kyunghee
K
Byun
Enkhjaigal
E
Bayarsaikhan
Daesik
D
Kim
Chae Young
CY
Kim
Inhee
I
Mook-Jung
Sun Ha
SH
Paek
Seung U
SU
Kim
Tadashi
T
Yamamoto
Moo-Ho
MH
Won
Byoung-Joon
BJ
Song
Young Mok
YM
Park
Bonghee
B
Lee
D000418:Albumins / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology*; D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D017127:Glycation End Products, Advanced / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008297:Male; D017628:Microglia / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects*; D018384:Oxidative Stress; D055503:Protein Multimerization; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism
D000418:Albumins; D016229:Amyloid beta-Peptides; D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic