Lovastatin Differentially Affects Neuronal Cholesterol and Amyloid‐β Production in vivo and in vitro

Mendoza-Oliva, Ayde; Ferrera, Patricia; Fragoso-Medina, Jorge; Arias, Clorinda

doi:10.1111/cns.12420

Cited by 12 publications

(6 citation statements)

References 77 publications

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“…These differences in the expression levels of HMGCR were analyzed by flow cytometry in infected cells treated with vehicle, MET or lovastatin. The results indicate that MET decreases HMGCR expression (Fig 4E) which is consistent with the results obtained by Madsen et al, 2015 whose demonstrated that MET decreases HMGCR expression and other genes related with lipid metabolism by transcriptional suppression of the steroid receptor coactivator 2 (SRC-2)[43] In contrast, lovastatin induced an increase in the amount of HMGCR (Fig 4E) confirming previous reports in hepatic and neuron cell lines [44]. This effect can be explained by the regulatory feedback induced by the reduction of intracellular cholesterol levels, which trigger HMGCR transcription [45].…”

Section: Resultssupporting

confidence: 91%

DENV up-regulates the HMG-CoA reductase activity through the impairment of AMPK phosphorylation: A potential antiviral target

Soto-Acosta¹,

et al. 2017

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Dengue is the most common mosquito-borne viral disease in humans. Changes of lipid-related metabolites in endoplasmic reticulum of dengue virus (DENV) infected cells have been associated with replicative complexes formation. Previously, we reported that DENV infection inhibits HMGCR phosphorylation generating a cholesterol-enriched cellular environment in order to favor viral replication. In this work, using enzymatic assays, ELISA, and WB we found a significant higher activity of HMGCR in DENV infected cells, associated with the inactivation of AMPK. AMPK activation by metformin declined the HMGCR activity suggesting that AMPK inactivation mediates the enhanced activity of HMGCR. A reduction on AMPK phosphorylation activity was observed in DENV infected cells at 12 and 24 hpi. HMGCR and cholesterol co-localized with viral proteins NS3, NS4A and E, suggesting a role for HMGCR and AMPK activity in the formation of DENV replicative complexes. Furthermore, metformin and lovastatin (HMGCR inhibitor) altered this co-localization as well as replicative complexes formation supporting that active HMGCR is required for replicative complexes formation. In agreement, metformin prompted a significant dose-dependent antiviral effect in DENV infected cells, while compound C (AMPK inhibitor) augmented the viral genome copies and the percentage of infected cells. The PP2A activity, the main modulating phosphatase of HMGCR, was not affected by DENV infection. These data demonstrate that the elevated activity of HMGCR observed in DENV infected cells is mediated through AMPK inhibition and not by increase in PP2A activity. Interestingly, the inhibition of this phosphatase showed an antiviral effect in an HMGCR-independent manner. These results suggest that DENV infection increases HMGCR activity through AMPK inactivation leading to higher cholesterol levels in endoplasmic reticulum necessary for replicative complexes formation. This work provides new information about the mechanisms involved in host lipid metabolism during DENV replicative cycle and identifies new potential antiviral targets for DENV replication.

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Section: Resultssupporting

confidence: 91%

DENV up-regulates the HMG-CoA reductase activity through the impairment of AMPK phosphorylation: A potential antiviral target

Soto-Acosta¹,

et al. 2017

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“… Husain et al (2017) showed that rosuvastatin inhibited Aβ aggregation and ameliorated cognitive impairment in an in vivo study. Additionally, although lovastatin was able to diminish Aβ levels in vitro , it was unable to produce any effect on Aβ levels in the brains of the mice, even though the mevalonate pathway was significantly modified ( Mendoza-Oliva et al, 2015 ). Conversely, Tg2576 mice that were treated with lovastatin (the most brain permeable statin) showed an increase in Aβ production and senile plaque deposition ( Park et al, 2003 ).…”

Section: Discussionmentioning

confidence: 99%

Effect of Cholesterol on Membrane Fluidity and Association of Aβ Oligomers and Subsequent Neuronal Damage: A Double-Edged Sword

Fernández-Pérez

Sepúlveda

Peters

et al. 2018

Front. Aging Neurosci.

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Background: The beta-amyloid peptide (Aβ) involved in Alzheimer’s disease (AD) has been described to associate/aggregate on the cell surface disrupting the membrane through pore formation and breakage. However, molecular determinants involved for this interaction (e.g., some physicochemical properties of the cell membrane) are largely unknown. Since cholesterol is an important molecule for membrane structure and fluidity, we examined the effect of varying cholesterol content with the association and membrane perforation by Aβ in cultured hippocampal neurons.Methods: To decrease or increase the levels of cholesterol in the membrane we used methyl-β-cyclodextrin (MβCD) and MβCD/cholesterol, respectively. We analyzed if membrane fluidity was affected using generalized polarization (GP) imaging and the fluorescent dye di-4-ANEPPDHQ. Additionally membrane association and perforation was assessed using immunocytochemistry and electrophysiological techniques, respectively.Results: The results showed that cholesterol removal decreased the macroscopic association of Aβ to neuronal membranes (fluorescent-puncta/20 μm: control = 18 ± 2 vs. MβCD = 10 ± 1, p < 0.05) and induced a facilitation of the membrane perforation by Aβ with respect to control cells (half-time for maximal charge transferred: control = 7.2 vs. MβCD = 4.4). Under this condition, we found an increase in membrane fluidity (46 ± 3.3% decrease in GP value, p < 0.001). On the contrary, increasing cholesterol levels incremented membrane rigidity (38 ± 2.7% increase in GP value, p < 0.001) and enhanced the association and clustering of Aβ (fluorescent-puncta/20 μm: control = 18 ± 2 vs. MβCD = 10 ± 1, p < 0.01), but inhibited membrane disruption.Conclusion: Our results strongly support the significance of plasma membrane organization in the toxic effects of Aβ in hippocampal neurons, since fluidity can regulate distribution and insertion of the Aβ peptide in the neuronal membrane.

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“…Cholesterol metabolism disorders in brain have been involved in neurodegenerative diseases such as AD . Scientific evidence has shown that the homeostasis of cholesterol in the brain is closely related to the metabolism of β‐amyloid peptides (Aβ), while the role of dietary cholesterol within the pathogenetic cascade of excessive Aβ deposition in the brain of AD needs to be further identified.…”

Section: Introductionmentioning

confidence: 99%

Increased Levels of 27‐Hydroxycholesterol Induced by Dietary Cholesterol in Brain Contribute to Learning and Memory Impairment in Rats

Zhang

et al. 2018

Molecular Nutrition Food Res

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Lovastatin Differentially Affects Neuronal Cholesterol and Amyloid‐β Production in vivo and in vitro

Abstract: Lovastatin modifies the mevalonate pathway without affecting cholesterol levels in vivo and is able to reduce Aβ levels only in vitro.

Cited by 12 publications

References 77 publications

DENV up-regulates the HMG-CoA reductase activity through the impairment of AMPK phosphorylation: A potential antiviral target

DENV up-regulates the HMG-CoA reductase activity through the impairment of AMPK phosphorylation: A potential antiviral target

Effect of Cholesterol on Membrane Fluidity and Association of Aβ Oligomers and Subsequent Neuronal Damage: A Double-Edged Sword

Increased Levels of 27‐Hydroxycholesterol Induced by Dietary Cholesterol in Brain Contribute to Learning and Memory Impairment in Rats

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