A Diet Enriched in Palmitate and Deficient in Linoleate Exacerbates Oxidative Stress and Amyloid-β Burden in the Hippocampus of 3xTg-AD Mouse Model of Alzheimer's Disease

Gurdeep Marwarha, Kate Claycombe-Larson, Jonah Lund, Jared Schommer, Othman Ghribi

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Epidemiological studies have suggested a positive correlation between saturated fat intake and the risk for developing Alzheimer's disease (AD). While diets-enriched in the saturated free fatty acid (sFFA) palmitate has been shown to induce cognitive dysfunction and AD-like pathology, polyunsaturated fatty acids (PUFA) such as linoleate have been suggested to protect against AD in mouse models. However, the underlying cellular and molecular mechanisms that mediate the deleterious effects of palmitate or the protective effects of linoleate remain to be characterized. We fed 9-month-old cohorts of triple transgenic AD mice (3xTg-AD) and their-matched controls with a palmitate-enriched/linoleate-deficient diet for three months and determined the impact of the diet on oxidative stress, Bace1 promoter transactivation status, and amyloid-β (Aβ) burden. The palmitate-enriched/linoleate-deficient diet causes a profound increase in oxidative stress burden characterized by significant oxidative damage to lipids, proteins, and nucleic acids concomitant with deficits in the endogenous antioxidant defense capacity in the hippocampi of 3xTg-AD mice. These effects were also associated with increased NF-κB transcriptional activity resulting in NF-κB-mediated transactivation of the Bace1 promoter that culminated in higher BACE1 expression and activity, and Aβ production. Our study unveils a novel mechanism by which a diet enriched in the sFFA palmitate and deficient in the PUFA linoleate exacerbates AD-like pathology involving signaling cross-talk between oxidative stress and NF-κB activation as a critical underlying factor in upregulating BACE1 activity and increasing Aβ burden.

Original languageEnglish (US)
Pages (from-to)219-237
Number of pages19
JournalJournal of Alzheimer's Disease
Volume68
Issue number1
DOIs
StatePublished - 2019

Keywords

  • Alzheimer's disease
  • BACE1
  • NF- κ B
  • amyloid-β
  • linoleate
  • oxidative stress
  • palmitate

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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