Palmitate Increases β-site AβPP-Cleavage Enzyme 1 Activity and Amyloid-β Genesis by Evoking Endoplasmic Reticulum Stress and Subsequent C/EBP Homologous Protein Activation

Abstract

Epidemiological studies implicate diets rich in saturated free fatty acids (sFFA) as a potential risk factor for developing Alzheimer’s disease (AD). In particular, high plasma levels of the sFFA palmitic acid (palmitate) were shown to inversely correlate with cognitive function. However, the cellular mechanisms by which sFFA may increase the risk for AD are not well known. Endoplasmic reticulum (ER) stress has emerged as one of the signaling pathways initiating and fostering the neurodegenerative changes in AD by increasing the aspartyl protease β-site AβPP cleaving enzyme 1 (BACE1) and amyloid-β (Aβ) genesis. In this study, we determined the extent to which palmitate increases BACE1 and Aβ levels in vitro and in vivo as well as the potential role of ER stress as cellular mechanism underlying palmitate effects. We demonstrate, in palmitate-treated SH-SY5Y neuroblastoma cells and in the hippocampi of palmitate-enriched diet-fed mice, that palmitate evokes the activation of the C/EBP Homologous Protein (CHOP), a transcription factor that is specifically responsive to ER stress. Induction of CHOP expression is associated with increased BACE1 mRNA, protein and activity levels, and subsequent enhanced amyloidogenic processing of amyloid-β protein precursor (AβPP) that culminates in a substantial increase in Aβ genesis. We further show that CHOP is an indispensable molecular mediator of palmitate-induced upregulation in BACE1 activity and Aβ genesis. Indeed, we show that Chop–/– mice and CHOP knocked-down SH-SY5Y neuroblastoma cells do not exhibit the same commensurate degree of palmitate-induced increase in BACE1 expression levels and Aβ genesis.

Retracted: Palmitate‐induced C/EBP homologous protein activation leads to NF‐κB‐mediated increase in BACE1 activity and amyloid beta genesis

“…Knocking-down CHOP expression in SH-SY5Y-APP Swe cells significantly attenuates the palmitate-induced increase in BACE1 expression and Ab genesis (Marwarha et al 2017e). Furthermore, Chop À/À mice fed a palmitate-enriched diet do not exhibit the same increase in BACE1 expression and Ab burden compared to the C57BL/6J wild-type mice fed a palmitate-enriched diet (Marwarha et al 2017e). However, questions still abounded with regard to the molecular mechanism(s) by which CHOP may induce the aforementioned effects.…”

“…NF-jB activation and transcriptional activity is required for the palmitate-induced CHOP-mediated increase in BACE1 expression and subsequent engenderment of Ab We determined the effects of palmitate treatment on NF-jB activation in SH-SY5Y-APP Swe human neuroblastoma cells (cells that stably express the Swedish KM670/671NL double mutant AbPP) as well as the effects of palmitateenriched diet on NF-jB activation in the mouse hippocampus. Our recent study showed that exogenous palmitate treatment, for 24 h at 100 lM terminal concentration, increases BACE1 expression in cultured SH-SY5Y-APP Swe cells (Marwarha et al 2017e). We therefore used this experimental paradigm, exogenous palmitate at 100 lM terminal concentration in the cell culture medium for 24 h, throughout this study.…”

“…We have recently shown that exogenous palmitate treatment and palmitate-enriched diet cause ER stress and induce CHOP expression that leads to an increase in BACE1 expression, enhanced BACE1 activity, and augmentation of Ab genesis in cultured SH-SY5Y-APP Swe cells and the mouse hippocampus, respectively (Marwarha et al 2017e). Knocking-down CHOP expression in SH-SY5Y-APP Swe cells significantly attenuates the palmitate-induced increase in BACE1 expression and Ab genesis (Marwarha et al 2017e). Furthermore, Chop À/À mice fed a palmitate-enriched diet do not exhibit the same increase in BACE1 expression and Ab burden compared to the C57BL/6J wild-type mice fed a palmitate-enriched diet (Marwarha et al 2017e).…”

“…No changes in food intake were observed (Marwarha et al 2017e). Body weights were measured every 2 weeks and reported in our previous study (Marwarha et al 2017e). Necropsy was performed at 12 months of age.…”

BAP31 deficiency contributes to the formation of amyloid‐β plaques in Alzheimer's disease by reducing the stability of RTN3

“…In addition, it is well known that BACE1 is a stress-induced protease whose activity has been shown to increase in many types of stress conditions. Furthermore, both in vitro and in vivo experiments revealed that activated caspase-3-dependent apoptosis resulted in an increase in BACE1 levels (34)(35)(36). Because BAP31 is related to ER quality control, the markers Figure 6.…”