<i>Retracted:</i> Palmitate‐induced C/EBP homologous protein activation leads to NF‐κB‐mediated increase in BACE1 activity and amyloid beta genesis

Marwarha, Gurdeep; Schommer, Jared; Lund, Jonah; Schommer, Trevor; Ghribi, Othman

doi:10.1111/jnc.14292

Cited by 19 publications

(17 citation statements)

References 109 publications

(246 reference statements)

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“…The effects of palmitateenriched diets and exogenous palmitate on the regulatory mechanisms involved in BACE1 expression and Aβ genesis have also not been exhaustively elucidated, with very few studies having determined the role of palmitate per se, and not high saturated fat diet, in the regulation of BACE1 expression and Aβ genesis. Our previous study has demonstrated that a palmitate-enriched diet, as well as treatment of cultured cells with exogenous palmitate, increases phosphorylation of tau, enhances BACE1 expression and the subsequent Aβ genesis, by evoking endoplasmic reticulum (ER) stress and C/EBP Homologous Protein (CHOP) activation [21,22,33]. Other studies have shown the effects of exogenous palmitate on BACE1 expression in primary cortical neuronal cultures and primary astrocytic cultures in vitro [34][35][36][37].…”

Section: Discussionmentioning

confidence: 99%

“…N2a-APP Swe/In cells were transfected with the designated vectors as previously described [24]. Transfected N2a-APP Swe/In cells were treated with BSA (bovine serum albumin)conjugated palmitate as shown previously [21,22]. Briefly, palmitate stock solution of 250mM was prepared in 100% ethanol.…”

Section: Cell Culture and Treatmentsmentioning

confidence: 99%

“…We first determined the effects of palmitate treatment on the expression levels and the transcriptional activities of SREBP1 and SREBP2 in cultured N2a-APP Swe/In mouse neuroblastoma cells that stably express the Swedish (KM595/596NL) and the Indiana (V642F) double mutant AβPP 695 . Our previous studies have demonstrated that palmitate treatment, for 24 hours at 100μM concentration, increases BACE1 expression in cultured SH-SY5Y-APP Swe cells [21,22]. In this study, we used the same validated treatment paradigm, palmitate conjugated to BSA (molar ratio 6:1) at a concentration of 100μM, to treat N2a-APP Swe/In mouse neuroblastoma cells for 24 hours.…”

Section: Palmitate Increases the Expression And Transcriptional Activmentioning

confidence: 99%

“…However, the role of linoleic acid per se on SREBP1 actication in vitro and in vivo should also be determined. Our previous study demonstrated that palmitate-enriched diet evokes ER stress and CHOP activation that results in enhanced BACE1 expression and activity leading to augmented Aβ burden in the hippocampus [21,22]. Interestingly, ER stress has been linked to SREBP1 activation in the β-cells of the pancreas [58][59][60].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

“…A recent study found that SREBP2 activity mediates the cholesterol-induced up-regulation in BACE1 expression [20]. We have shown that palmitate-enriched diets and exogenous palmitate-treatment of cells results in increased BACE1 expression and activity leading to increased Aβ genesis [21,22]. However, the extent to which palmitate modulates the expression and activities of SREBP in the brain is not known.…”

Section: Introductionmentioning

confidence: 96%

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

et al. 2018

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Cell Culture and Treatmentsmentioning

confidence: 99%

Section: Palmitate Increases the Expression And Transcriptional Activmentioning

confidence: 99%

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

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

et al. 2018

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

Syeda

Cannon

2021

J Biochem & Molecular Tox

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Alzheimer's disease (AD) is a major public health crisis due to devastating cognitive symptoms, a lack of curative treatments, and increasing prevalence. Most cases are sporadic (>95% of cases) after the age of 65 years, implicating an important role of environmental factors in disease pathogenesis. Environmental neurotoxicants have been implicated in neurodegenerative disorders including Parkinson's Disease and AD. Animal models of AD and in vitro studies have shed light on potential neuropathological mechanisms, yet the biochemical and molecular underpinnings of AD‐relevant environmental neurotoxicity remain poorly understood. Beta‐site amyloid precursor protein cleaving enzyme 1 (BACE1) is a potentially critical pathogenic target of environmentally induced neurotoxicity. BACE1 clearly has a critical role in AD pathophysiology: It is required for amyloid beta production and expression and activity of BACE1 are increased in the AD brain. Though the literature on BACE1 in response to environmental insults is limited, current studies, along with extensive AD neurobiology literature suggest that BACE1 deserves attention as an important neurotoxic target. Here, we critically review research on environmental neurotoxicants such as metals, pesticides, herbicides, fungicides, polyfluoroalkyl substances, heterocyclic aromatic amines, advanced glycation end products, and acrolein that modulate BACE1 and potential mechanisms of action. Though more research is needed to clearly understand whether BACE1 is a critical mediator of AD‐relevant neurotoxicity, available reports provide convincing evidence that BACE1 is altered by environmental risk factors associated with AD pathology, implying that BACE1 inhibition and its use as a biomarker should be considered in AD management and research.

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Palmitic Acid-Induced NAD+ Depletion is Associated with the Reduced Function of SIRT1 and Increased Expression of BACE1 in Hippocampal Neurons

et al. 2019

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Increased levels of circulating fatty acids, such as palmitic acid (PA), are associated with the development of obesity, insulin resistance, type-2 diabetes and metabolic syndrome. Furthermore, these diseases are linked to an increased risk of cancer, cardiovascular diseases, mild cognitive impairment and even Alzheimer's disease (AD). However, the precise actions of elevated PA levels on neurons and their association with neuronal metabolic disruption that leads to the expression of pathological markers of AD, such as the overproduction and accumulation of the amyloid-β peptide, represent an area of intense investigation. A possible molecular mechanism involved in the effects of PA may be through dysfunction of the NAD + sensor enzyme, SIRT1. Therefore, the aim of the present study was to analyze the relationship between the effects of PA metabolism on the function of SIRT1 and the upregulation of BACE1 in cultured hippocampal neurons. PA reduced the total amount of NAD + in neurons that caused an increase in p65 K310 acetylation due to inhibition of SIRT1 activity and low protein content. Furthermore, BACE1 protein and its activity were increased, and BACE1 was relocated in neurites after PA exposure.

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Retracted: Palmitate‐induced C/EBP homologous protein activation leads to NF‐κB‐mediated increase in BACE1 activity and amyloid beta genesis

Cited by 19 publications

References 109 publications

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

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

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

Palmitic Acid-Induced NAD+ Depletion is Associated with the Reduced Function of SIRT1 and Increased Expression of BACE1 in Hippocampal Neurons

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