Location: Healthy Body Weight ResearchTitle: Palmitate-enriched diet exacerbates oxidative stress and Amyloid beta burden in the hippocampus of 3xTg-AD mouse model
|MARWARHA, GURDEEP - University Of North Dakota|
|LUND, JONAH - University Of North Dakota|
|SCHOMMER, JARED - University Of North Dakota|
|GHRIBI, OTHMAN - University Of North Dakota|
Submitted to: Journal of Alzheimer's Disease
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/18/2018
Publication Date: 3/12/2019
Citation: Marwarha, G., Larson, K.J., Lund, J., Schommer, J., Ghribi, O. 2019. Palmitate-enriched diet exacerbates oxidative stress and Amyloid beta burden in the hippocampus of 3xTg-AD mouse model. Journal of Alzheimer's Disease. https://doi.org/10.3233/JAD-180835.
Interpretive Summary: It is known that diet rich in saturated fat such as palmitate increases risk for developing Alzheimer’s disease (AD). Patients with AD often have significant accumulation of amyloid-beta in the brain and amyloid-beta synthesis regulator called BACE1. Using genetically engineered transgenic mice of AD (3xTg-AD) and controls, we fed these mice a palmitate-enriched diet for three months. Results showed that these mice have palmitate-enriched diet-induced increase in oxidative stress that is also associated with increased activity of transcription factor called NF-Kappa B at the transcription control region of Bace1 gene leading to higher BACE1 gene expression and activity, as well as increased and amyloid-beta production. Our study unveils a novel signaling cross-talk between oxidative stress and NF-Kappa B activation as a critical underlying factor in the palmitate-enriched diet induced up-regulation in BACE1 expression.
Technical Abstract: Epidemiological studies have suggest a direct positive correlation between saturated fat intake and the risk for developing Alzheimer’s disease (AD). Diets-enriched in the saturated free fatty acid (sFFA) palmitate has also been shown to induce cognitive dysfunction and AD-like pathology in mouse models. However, the underlying cellular and molecular mechanisms that mediate the deleterious effects of palmitate-enriched diets remain to be characterized. We fed nine-month old cohorts of triple transgenic AD mice (3xTg-AD) and their-matched controls with a palmitate-enriched diet for three months and performed NF- Kappa B transcriptional activity assays and Chromatin Immunoprecipitation (ChIP) analysis to determine the impact of the palmitate-enriched diet-induced oxidative stress on NF- Kappa B signaling and Bace1 promoter transactivation status. Palmitate-enriched 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. This palmitate-enriched diet-induced increase in oxidative stress is associated with increased NF- Kappa B transcriptional activity resulting in NF- Kappa B -mediated transactivation of the Bace1 promoter that culminates in higher BACE1 expression and activity, and Aß production. Our study unveils a novel signaling cross-talk between oxidative stress and NF- Kappa B activation as a critical underlying factor in the palmitate-enriched diet induced up-regulation in BACE1 expression and the subsequent increase in ABeta burden.