High glucose upregulates BACE1-mediated Aβ production through ROS-dependent HIF-1α and LXRα/ABCA1-regulated lipid raft reorganization in SK-N-MC cells.
There is an accumulation of evidence indicating that the risk of Alzheimer's disease is associated with diabetes mellitus, an indicator of high glucose concentrations in blood plasma. This study investigated the effect of high glucose on BACE1 expression and amyloidogenesis in vivo, and we present details of the mechanism associated with those effects. Our results, using ZLC and ZDF rat models, showed that ZDF rats have high levels of amyloid-beta (Aβ), phosphorylated tau, BACE1, and APP-C99. In vitro result with mouse hippocampal neuron and SK-N-MC, high glucose stimulated Aβ secretion and apoptosis in a dose-dependent manner. In addition, high glucose increased BACE1 and APP-C99 expressions, which were reversed by a reactive oxygen species (ROS) scavenger. Indeed, high glucose increased intracellular ROS levels and HIF-1α expression, associated with regulation of BACE1 and Liver X Receptor α (LXRα). In addition, high glucose induced ATP-binding cassette transporter A1 (ABCA1) down-regulation, was associated with LXR-induced lipid raft reorganization and BACE1 localization on the lipid raft. Furthermore, silencing of BACE1 expression was shown to regulate Aβ secretion and apoptosis of SK-N-MC. In conclusion, high glucose upregulates BACE1 expression and activity through HIF-1α and LXRα/ABCA1-regulated lipid raft reorganization, leading to Aβ production and apoptosis of SK-N-MC.
Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science and BK21 PLUS Program for Creative Veterinary Science Research Center, Seoul National University, Seoul 08826, Korea.
Hyun Jik
HJ
Lee
Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Korea.
Jung Min
JM
Ryu
Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science and BK21 PLUS Program for Creative Veterinary Science Research Center, Seoul National University, Seoul 08826, Korea.
Young Hyun
YH
Jung
Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science and BK21 PLUS Program for Creative Veterinary Science Research Center, Seoul National University, Seoul 08826, Korea.
Sei-Jung
SJ
Lee
Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science and BK21 PLUS Program for Creative Veterinary Science Research Center, Seoul National University, Seoul 08826, Korea.
Jeong Yeon
JY
Kim
Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea.|Department of Biochemistry, Soonchunhyang University College of Medicine, Cheonan, 330-930, Republic of Korea.
Sang Hun
SH
Lee
BK21 PLUS Program for Creative Veterinary Science Research, and Research Institute for Veterinary Science; Seoul National University and Korea Mouse Phenotyping Center (KMPC), Seoul, Korea.|Department of Anatomy and Cell Biology; Korea Mouse Phenotyping Center (KMPC); College of Veterinary Medicine; Seoul National University, Seoul, Korea.
In Koo
IK
Hwang
BK21 PLUS Program for Creative Veterinary Science Research, and Research Institute for Veterinary Science; Seoul National University and Korea Mouse Phenotyping Center (KMPC), Seoul, Korea.|Department of Anatomy and Cell Biology; Korea Mouse Phenotyping Center (KMPC); College of Veterinary Medicine; Seoul National University, Seoul, Korea.
Je Kyung
JK
Seong
Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science and BK21 PLUS Program for Creative Veterinary Science Research Center, Seoul National University, Seoul 08826, Korea.
Ho Jae
HJ
Han
D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000544:Alzheimer Disease / Q000097:blood / Q000209:etiology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D001786:Blood Glucose; D018938:Caco-2 Cells; D048909:Diabetes Complications / Q000097:blood; D003920:Diabetes Mellitus / Q000097:blood; D005260:Female; D005947:Glucose / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D000071518:Liver X Receptors / Q000378:metabolism; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000502:physiology; D018384:Oxidative Stress; D011924:Rats, Zucker; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015854:Up-Regulation
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D016229:Amyloid beta-Peptides; D001786:Blood Glucose; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000071518:Liver X Receptors; D017382:Reactive Oxygen Species; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D005947:Glucose