Palmitate-Induced SREBP1 Expression and Activation Underlies the Increased BACE 1 Activity and Amyloid Beta Genesis

Abstract

Numerous cross-sectional and longitudinal studies have implicated saturated fat-enriched diets in the etio-pathogenesis of Alzheimer's disease (AD). Emerging evidence shows that saturated fatenriched diets, such as palmitate-enriched diets, increase amyloid-beta (Aβ) production, the histopathological hallmark of AD. However, the molecular mechanisms that underlie the deleterious effects of palmitate-enriched diets in the augmentation of Aβ genesis are yet to be characterized. Sterol Response Element binding protein 1 (SREBP1) is a transcription factor that is modulated by saturated fatty acids, such as palmitate, and consequently regulates the expression of genes that code for proteins involved in almost all facets of lipid metabolism. Herein, we determined the role of changes in SREBP1 expression and transcriptional activity in the palmitateinduced effects on Aβ genesis and BACE1 expression, the enzyme that catalyzes the rate limiting step in Aβ biosynthesis. We demonstrate that palmitate-induced SREBP1 activation, directly regulates BACE1 expression at the transcriptional level in the mouse hippocampus and mouse Neuro-2a (N2a) neuroblastoma cells. Chromatin Immunoprecipitation (ChIP) studies show that palmitate increases the binding of SREBP1 to the Bace1 promoter region in the mouse hippocampus and mouse N2a neuroblastoma cells. Ectopic expression of the dominant negative SREBP1 mutant and knocking-down SREBP1 expression, significantly reduced the palmitateinduced increase in BACE1 expression and subsequent Aβ genesis in mouse N2a neuroblastoma cells. Our study unveils SREBP1 activation as a novel molecular player in the palmitate-induced up-regulation of BACE1 expression and subsequent Aβ genesis.

Polyunsaturated Fatty Acid Composition of Cerebrospinal Fluid Fractions Shows Their Contribution to Cognitive Resilience of a Pre-symptomatic Alzheimer’s Disease Cohort

“…Disruption of membrane components, including fatty acid composition, can alter interactions with these proteins. For example, physical measurements show that the ratio of saturated to PUFA influences how Aβ 42 binds to BACE (Cole and Frautschy, 2006;Grimm et al, 2011;Eto et al, 2019;Marwarha et al, 2019). Similar changes in fatty acids that we measured in CSF fractions, and their correlation with Aβ 42 and T-tau in our clinical groups confirm the role of fatty acids in AD severity and progression.…”

Environmental exposures and the etiopathogenesis of Alzheimer's disease: The potential role of BACE1 as a critical neurotoxic target

“…They are known to promote amyloidogenic cleavage of APP by BACE1. [241][242][243][244][245][246] Cooking and processing of food at a high temperature can produce toxic compounds, such as advanced glycation end products (AGEs), heterocyclic aromatic amines (HAAs), acrylamide, and acrolein. [247][248][249][250][251] The potential role of dietary toxins is being studied for AD relevance as they are encountered in higher doses and more frequently through one's life span compared to other environmental contaminants.…”

Exercise training modulates adipokine dysregulations in metabolic syndrome

“… 26 For example, the lipolytic action of exercise needs phosphorylation of 5′ Adenosine Monophosphate-Activated Protein Kinase (AMPK) to reduce the Sterol Regulatory Element-Binding Protein 1c (SREBP-1c). 27 , 28 AMPK inhibits hepatic TG synthesis suppressing acetyl-CoA carboxylase, 29 and promotes fatty acid oxidation and reduction in fat mass. 30 , 31 Other beneficial effects of exercise are related to increased peripheral glucose uptake 32 which takes place via activating PI3K, and translocating the Glucose Transporter Type 4 (GLUT4) into the skeletal muscles cell membranes, 33 and also increasing AMPK activity, which increases insulin sensitivity.…”