Aβ inhibits SREBP-2 activation through Akt inhibition

Mohamed, Ahmed F.; Viveiros, Anissa; Williams, Kathleen; Chaves, E

doi:10.1194/jlr.m076703

Cited by 19 publications

(12 citation statements)

References 103 publications

(139 reference statements)

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“…Aging has been found to lead to decreased cholesterol synthesis in astrocytes, which may contribute to the synaptic and neuronal degeneration associated with senescence (Boisvert et al, 2018). In addition, oligomeric Aβ inhibits cholesterol synthesis, as observed in mouse cerebrocortical cells (Mohamed et al, 2018). GT1-7 hypothalamic cells were manipulated to decrease cholesterol production, which resulted in increased apoptosis in the presence of Aβ (Fukui et al, 2015).…”

Section: Altered Cholesterol Levels May Modulate Aβ Actionmentioning

confidence: 99%

Cholesterol as a key player in amyloid β-mediated toxicity in Alzheimer’s disease

Rudajev

Novotný

2022

Front. Mol. Neurosci.

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Alzheimer’s disease (AD) is a neurodegenerative disorder that is one of the most devastating and widespread diseases worldwide, mainly affecting the aging population. One of the key factors contributing to AD-related neurotoxicity is the production and aggregation of amyloid β (Aβ). Many studies have shown the ability of Aβ to bind to the cell membrane and disrupt its structure, leading to cell death. Because amyloid damage affects different parts of the brain differently, it seems likely that not only Aβ but also the nature of the membrane interface with which the amyloid interacts, helps determine the final neurotoxic effect. Because cholesterol is the dominant component of the plasma membrane, it plays an important role in Aβ-induced toxicity. Elevated cholesterol levels and their regulation by statins have been shown to be important factors influencing the progression of neurodegeneration. However, data from many studies have shown that cholesterol has both neuroprotective and aggravating effects in relation to the development of AD. In this review, we attempt to summarize recent findings on the role of cholesterol in Aβ toxicity mediated by membrane binding in the pathogenesis of AD and to consider it in the broader context of the lipid composition of cell membranes.

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Section: Altered Cholesterol Levels May Modulate Aβ Actionmentioning

confidence: 99%

Cholesterol as a key player in amyloid β-mediated toxicity in Alzheimer’s disease

Rudajev

Novotný

2022

Front. Mol. Neurosci.

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“…The young brain may have mechanisms in place to cope with inefficient APOE4 lipid transport; but aging leads to decreased cholesterol synthesis in astrocytes (Boisvert et al, 2018), which, when combined with lower efflux from APOE4, could tip the balance and culminate in neuronal lipid deficits. Furthermore, Aβ inhibits SREBP2 in primary cultured cells from mouse cortex (Mohamed et al, 2018), suggesting that amyloid deposition could make neurons even more dependent on astrocytic lipids, which would be lacking in ε4 carriers. Although cholesterol has been the most extensively studied, changes in other lipid classes are also observed in serum samples from AD patients, including sterols, sphingomyelin, phosphatidylcholine, glycerophosphoethanolamine, lysophosphatidylcholine, diacylglycerols, and triacylglycerols (Anand et al, 2017); therefore, APOE4 status could exacerbate other age-related changes in lipid homeostasis.…”

Section: Apoe and Astrocyte Bioenergeticsmentioning

confidence: 99%

The Role of APOE4 in Disrupting the Homeostatic Functions of Astrocytes and Microglia in Aging and Alzheimer’s Disease

Fernandez

Hamby

McReynolds

et al. 2019

Front. Aging Neurosci.

195

173

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APOE4 is the greatest genetic risk factor for late-onset Alzheimer’s disease (AD), increasing the risk of developing the disease by 3-fold in the 14% of the population that are carriers. Despite 25 years of research, the exact mechanisms underlying how APOE4 contributes to AD pathogenesis remain incompletely defined. APOE in the brain is primarily expressed by astrocytes and microglia, cell types that are now widely appreciated to play key roles in the pathogenesis of AD; thus, a picture is emerging wherein APOE4 disrupts normal glial cell biology, intersecting with changes that occur during normal aging to ultimately cause neurodegeneration and cognitive dysfunction. This review article will summarize how APOE4 alters specific pathways in astrocytes and microglia in the context of AD and the aging brain. APOE itself, as a secreted lipoprotein without enzymatic activity, may prove challenging to directly target therapeutically in the classical sense. Therefore, a deeper understanding of the underlying pathways responsible for APOE4 toxicity is needed so that more tractable pathways and drug targets can be identified to reduce APOE4-mediated disease risk.

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“…Changes in protein prenylation can be assessed by analyzing the lipophilic properties of the protein using Triton X-114 extraction. This method was recently applied to study prenylation of Rab7 in neurons (Mohamed et al. , 2018).…”

Section: Resultsmentioning

confidence: 99%

FBXW7 regulates endothelial barrier function by suppression of the cholesterol synthesis pathway and prenylation of RhoB

Pronk¹,

Majolée²,

Loregger

et al. 2019

MBoC

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Rho GTPases control both the actin cytoskeleton and adherens junction stability and are recognized as essential regulators of endothelial barrier function. They act as molecular switches and are primarily regulated by the exchange of GDP and GTP. However, posttranslational modifications such as phosphorylation, prenylation, and ubiquitination can additionally alter their localization, stability, and activity. F-box proteins are involved in the recognition of substrate proteins predestined for ubiquitination and subsequent degradation. Given the importance of ubiquitination, we studied the effect of the loss of 62 members of the F-box protein family on endothelial barrier function in human umbilical vein endothelial cells. Endothelial barrier function was quantified by electrical cell impedance sensing and macromolecule passage assay. Our RNA interference–based screen identified FBXW7 as a key regulator of endothelial barrier function. Mechanistically, loss of FBXW7 induced the accumulation of the RhoB GTPase in endothelial cells, resulting in their increased contractility and permeability. FBXW7 knockdown induced activation of the cholesterol biosynthesis pathway and changed the prenylation of RhoB. This effect was reversed by farnesyl transferase inhibitors and by the addition of geranylgeranyl pyrophosphate. In summary, this study identifies FBXW7 as a novel regulator of endothelial barrier function in vitro. Loss of FBXW7 indirectly modulates RhoB activity via alteration of the cholesterol biosynthesis pathway and, consequently, of the prenylation status and activity of RhoB, resulting in increased contractility and disruption of the endothelial barrier.

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Aβ inhibits SREBP-2 activation through Akt inhibition

Cited by 19 publications

References 103 publications

Cholesterol as a key player in amyloid β-mediated toxicity in Alzheimer’s disease

Cholesterol as a key player in amyloid β-mediated toxicity in Alzheimer’s disease

The Role of APOE4 in Disrupting the Homeostatic Functions of Astrocytes and Microglia in Aging and Alzheimer’s Disease

FBXW7 regulates endothelial barrier function by suppression of the cholesterol synthesis pathway and prenylation of RhoB

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