Journal
JOURNAL OF NEUROCHEMISTRY
Volume 144, Issue 6, Pages 761-779Publisher
WILEY
DOI: 10.1111/jnc.14292
Keywords
Alzheimer's disease; C/EBP homologous protein; endoplasmic reticulum stress; nuclear factor of kappa-light-polypeptide gene enhancer of activated B cells; palmitic acid; beta-site APP cleaving enzyme 1
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Funding
- NIA NIH HHS [R01 AG045264] Funding Source: Medline
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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 (A beta) is considered the core pathological molecular event in the pathogenesis of AD. The rate-limiting step in Ab genesis from amyloid-beta precursor protein (A beta PP) 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 Ab production. We demonstrate that a palmitate-enriched diet and exogenous palmitate treatment evoke an increase in BACE1 expression and activity leading to enhanced Ab genesis in the mouse brain and SHSY5Y-APP(Swe) cells, respectively, through the activation of the transcription factor NF-kappa B. Chromatin immunoprecipitation (ChIP) assays and luciferase reporter assays revealed that palmitate enhances BACE1 expression by increasing the binding of NF-kappa B 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-kappa B activation, as CHOP knock-down cells and Chop(-/-) mice do not exhibit the samedegree of NF-kappa B activation in response to the palmitate challenge. Our study delineates a novel CHOP-NF-kappa B signaling pathway that mediates palmitate-induced up-regulation of BACE1 expression and A beta genesis.
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