High glucose upregulates BACE1-mediated Aβ production through ROS-dependent HIF-1α and LXRα/ABCA1-regulated lipid raft reorganization in SK-N-MC cells

Sci Rep. 2016 Nov 10:6:36746. doi: 10.1038/srep36746.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1 / metabolism
  • Alzheimer Disease / blood
  • Alzheimer Disease / etiology
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / biosynthesis*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Apoptosis
  • Aspartic Acid Endopeptidases / genetics
  • Aspartic Acid Endopeptidases / metabolism
  • Blood Glucose
  • Caco-2 Cells
  • Diabetes Complications / blood
  • Diabetes Mellitus / blood
  • Female
  • Glucose / physiology*
  • Hippocampus / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Liver X Receptors / metabolism
  • Male
  • Membrane Microdomains / metabolism*
  • Mice
  • Neurons / physiology
  • Oxidative Stress
  • Rats, Zucker
  • Reactive Oxygen Species / metabolism*
  • Up-Regulation

Substances

  • ABCA1 protein, human
  • ATP Binding Cassette Transporter 1
  • Amyloid beta-Peptides
  • Blood Glucose
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Liver X Receptors
  • Reactive Oxygen Species
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Glucose