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

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.

Neurotropin® alleviates hippocampal neuron damage through a HIF‐1α/MAPK pathway

“…It has been found that an upregulation of HIF‐1α enhanced expression of BACE1, while the HIF‐1α knock‐out mouse demonstrated a downregulation in BACE1 expression in hippocampus . Recently, another investigation reported that high glucose‐induced oxidative stress condition stimulated Aβ production in ZDF rats through HIF‐1α‐dependent direct expression of BACE1, indicating a close link between HIF‐1α and Aβ formation under oxidative conditions . However, whether NTP plays an important role in the regulation of HIF‐1α requires further investigation.…”

“…According to our previous study, 13 the viabilities of HT22 cells could significantly decrease when the cells were exposed to 40 μmol/L Aβ 25-35 for 24 hours. Thus, we selected 40 μmol/L as the optimal concentration of Aβ [25][26][27][28][29][30][31][32][33][34][35] for our subsequent research. HT22 cells were preconditioned with specified doses of NTP for 16 hours and subsequently treated with or without 40 μmol/L Aβ 25-35 for 24 hours.…”

“…As reported, Aβ [25][26][27][28][29][30][31][32][33][34][35] is the shortest active fragment with similar neurotoxicity effect to a full-length Aβ. 10 In addition, Aβ [25][26][27][28][29][30][31][32][33][34][35] can be easily synthesized and has been widely used in scientific researches. [11][12][13] Thus, we choose this fragment in our research.…”

Amyloid precursor protein in pancreatic islets

“…Several lines of evidence suggest that culturing cells in high glucose concentrations can alter APP processing and affect APP protein levels (Lee, et al 2016; Yang, et al 2013). Additionally, a recent study utilizing glucose clamps to sustain hyperglycemia demonstrates that increasing glucose concentrations in vivo alters APP processing to influence Aβ levels in the CSF (Macauley, et al 2015).…”

Enhancement of high glucose‐induced PINK1 expression by melatonin stimulates neuronal cell survival: Involvement of MT2/Akt/NF‐κB pathway

“…The SK‐N‐MC and SH‐SY5Y neuroblastoma cell lines and mouse hippocampal neurons have been widely used for investigating the pathogenesis of neuronal diseases related to hyperglycemia and DM . Moreover, use of the neuronal cell lines has advantages in studies into the identification of molecular mechanism due to their high homogeneity and reproducibility.…”