| First Author | Marwarha G | Year | 2018 |
| Journal | J Neurochem | Volume | 144 |
| Issue | 6 | Pages | 761-779 |
| PubMed ID | 29315574 | Mgi Jnum | J:260623 |
| Mgi Id | MGI:6151718 | Doi | 10.1111/jnc.14292 |
| Citation | Marwarha G, et al. (2018) Palmitate-induced C/EBP homologous protein activation leads to NF-kappaB-mediated increase in BACE1 activity and amyloid beta genesis. J Neurochem 144(6):761-779 |
| abstractText | 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 (Abeta) is considered the core pathological molecular event in the pathogenesis of AD. The rate-limiting step in Abeta genesis from amyloid-beta precursor protein (AbetaPP) is catalyzed by the enzyme beta-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 Abeta production. We demonstrate that a palmitate-enriched diet and exogenous palmitate treatment evoke an increase in BACE1 expression and activity leading to enhanced Abeta genesis in the mouse brain and SH-SY5Y-APPSwe cells, respectively, through the activation of the transcription factor NF-kappaB. Chromatin immunoprecipitation (ChIP) assays and luciferase reporter assays revealed that palmitate enhances BACE1 expression by increasing the binding of NF-kappaB 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-kappaB activation, as CHOP knock-down cells and Chop(-/-) mice do not exhibit the same degree of NF-kappaB activation in response to the palmitate challenge. Our study delineates a novel CHOP-NF-kappaB signaling pathway that mediates palmitate-induced up-regulation of BACE1 expression and Abeta genesis. |
