Palmitate-induced C/EBP homologous protein activation leads to NF-κB-mediated increase in BACE1 activity and amyloid beta genesis.
The etiology of Alzheimer's disease (AD) is egregiously comprehended, but epidemiological studies have posited that diets rich in the saturated fatty acid palmitic acid (palmitate) are a significant risk factor. The production and accumulation of amyloid beta peptide (Aβ) is considered the core pathological molecular event in the pathogenesis of AD. The rate-limiting step in Aβ genesis from amyloid-β precursor protein (AβPP) is catalyzed by the enzyme β-site amyloid precursor protein cleaving enzyme 1 (BACE1), the expression and enzymatic activity of which is significantly up-regulated in the AD brain. In this study, we determined the molecular mechanisms that potentially underlie the palmitate-induced up-regulation in BACE1 expression and augmented Aβ production. We demonstrate that a palmitate-enriched diet and exogenous palmitate treatment evoke an increase in BACE1 expression and activity leading to enhanced Aβ genesis in the mouse brain and SH-SY5Y-APPSwe cells, respectively, through the activation of the transcription factor NF-κB. Chromatin immunoprecipitation (ChIP) assays and luciferase reporter assays revealed that palmitate enhances BACE1 expression by increasing the binding of NF-κB in the BACE1 promoter followed by an enhancement in the transactivation of the BACE1 promoter. Elucidation and delineation of upstream molecular events unveiled a critical role of the endoplasmic reticulum stress-associated transcription factor, C/EBP homologous protein (CHOP) in the palmitate-induced NF-κB activation, as CHOP knock-down cells and Chop-/- mice do not exhibit the same degree of NF-κB activation in response to the palmitate challenge. Our study delineates a novel CHOP-NF-κB signaling pathway that mediates palmitate-induced up-regulation of BACE1 expression and Aβ genesis.
['Marwarha|Gurdeep|G|', 'Schommer|Jared|J|', 'Lund|Jonah|J|', 'Schommer|Trevor|T|', 'Ghribi|Othman|O|0000-0002-4683-1286']
D000544:Alzheimer Disease D053829:Amyloid Precursor Protein Secretases D016229:Amyloid beta-Peptides D000818:Animals D017209:Apoptosis D016282:Aspartic Acid Endopeptidases D045744:Cell Line, Tumor D005786:Gene Expression Regulation D006801:Humans D008297:Male D008810:Mice, Inbred C57BL D016328:NF-kappa B D019308:Palmitic Acid D015398:Signal Transduction D051742:Transcription Factor CHOP
C/EBP homologous protein Alzheimer's disease palmitic acid endoplasmic reticulum stress nuclear factor of kappa-light-polypeptide gene enhancer of activated B cells β-site APP cleaving enzyme 1