Direct evidence of abca1-mediated efflux of cholesterol at the mouse blood–brain barrier

Minh, Tuan Nguyen; Ouellet, Mélissa; Calon, Frédéric; Chimini, Giovanna; Chacun, Hélène; Farinotti, Robert; Bourasset, Fanchon

doi:10.1007/s11010-011-0910-6

Cited by 32 publications

(26 citation statements)

References 41 publications

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“…The cholesterol efflux is preferentially directed to the apical compartment (the blood side) and probably helps regulating the cerebral pool of cholesterol. Taken as a whole, these data strongly reinforce the hypothesis whereby the human BBB is involved in cholesterol homeostasis in the brain and the periphery [29,31,42,62]. Thus, we hypothesized that if the physiology of the BBB is altered (as in several murine models of AD [19][20][21]50]), bexarotene will have less effect on the brain's cholesterol metabolism.…”

Section: Discussionsupporting

confidence: 68%

“…The brain endothelial cells (ECs) composing the BBB express several receptors, enzymes, and transporters that regulate brain homeostasis and composition of the milieu. We and others have demonstrated in vivo, in situ, and in vitro that ABCA1 is the major protagonist in the exchange of cholesterol between the brain and the blood [29][30][31]. The BBB also participates in the regulation of the brain pool of A␤ peptides in general and the re-entry of these peptides into the brain in particular [32][33][34][35][36].…”

Section: Introductionmentioning

confidence: 92%

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Bexarotene Promotes Cholesterol Efflux and Restricts Apical-to-Basolateral Transport of Amyloid-β Peptides in an In Vitro Model of the Human Blood-Brain Barrier

Kuntz

Candela

Saint-Pol

et al. 2015

JAD

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Abstract.One of the prime features of Alzheimer's disease (AD) is the excessive accumulation of amyloid-␤ (A␤) peptides in the brain. Several recent studies suggest that this phenomenon results from the dysregulation of cholesterol homeostasis in the brain and impaired bidirectional A␤ exchange between blood and brain. These mechanisms appear to be closely related and are controlled by the blood-brain barrier (BBB) at the brain microvessel level. In animal models of AD, the anticancer drug bexarotene (a retinoid X receptor agonist) has been found to restore cognitive functions and decrease the brain amyloid burden by regulating cholesterol homeostasis. However, the drug's therapeutic effect is subject to debate and the exact mechanism of action has not been characterized. Therefore, the objective of this present study was to determine bexarotene's effects on the BBB. Using an in vitro model of the human BBB, we investigated the drug's effects on cholesterol exchange between abluminal and luminal compartments and the apical-to-basolateral transport of A␤ peptides across the BBB. Our results demonstrated that bexarotene induces the expression of ABCA1 but not ApoE. This upregulation correlates with an increase in ApoE2-, ApoE4-, ApoA-I-, and HDL-mediated cholesterol efflux. Regarding the transport of A␤ peptides, bexarotene increases the expression of ABCB1, which in turn decreases A␤ apical-to-basolateral transport. Our results showed that bexarotene not only promotes the cholesterol exchange between the brain and the blood but also decreases the influx of A␤ peptides across BBB, suggesting that bexarotene is a promising drug candidate for the treatment of AD.

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Section: Discussionsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 92%

Bexarotene Promotes Cholesterol Efflux and Restricts Apical-to-Basolateral Transport of Amyloid-β Peptides in an In Vitro Model of the Human Blood-Brain Barrier

Kuntz

Candela

Saint-Pol

et al. 2015

JAD

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“…The latter are important for the development, maturation, and maintenance of the properties of BBB [25,26]. In both in vitro and in vivo experiments, we and others have already demonstrated that BCECs and pericytes express LXR and their target genes (such as ABCA1) [21][22][23][27][28][29][30]. Given that as much as 6 to 7 mg of 24S-OH-chol crosses the BBB per 24 h [5], it is not surprising that this oxysterol increases the expression of ABCA1 and raises cholesterol release from BCECs to apoA-I and HDL particles [23,28,29].…”

Section: Introductionmentioning

confidence: 80%

“…Given that the BBB is thought to be involved in the complex process of brain cholesterol homeostasis [21][22][23] and in A␤ peptide exchanges between the blood and the brain (reviewed in [24]), it is essential to investigate the role of LXRs at the BBB level. The BBB is composed of brain capillary endothelial cells (BCECs), which are surrounded by pericytes.…”

Section: Introductionmentioning

confidence: 99%

Brain Pericytes ABCA1 Expression Mediates Cholesterol Efflux but not Cellular Amyloid-β Peptide Accumulation

Saint-Pol

Vandenhaute

Boucau

et al. 2012

JAD

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In brain, excess cholesterol is metabolized into 24S-hydroxycholesterol (24S-OH-chol) and eliminated into the circulation across the blood-brain barrier. 24S-OH-chol is a natural agonist of the nuclear liver X receptors (LXRs) involved in peripheral cholesterol homeostasis. The effects of this oxysterol on the pericytes embedded in the basal lamina of this barrier (close to the brain compartment) have not been previously studied. We used primary cultures of brain pericytes to demonstrate that the latter express LXR nuclear receptors and their target gene ATP-binding cassette, sub-family A, member 1 (ABCA1), known to be one of the major transporters involved in peripheral lipid homeostasis. Treatment with 24S-OH-chol caused an increase in ABCA1 expression that correlated with a reverse cholesterol transfer to apolipoprotein E, apolipoprotein A-I, and high density lipoprotein particles. Inhibition of ABCA1 decreased this efflux. As pericytes are able to internalize the amyloid-β peptides which accumulate in brain of Alzheimer's disease patients, we then investigated the effects of 24S-OH-chol on this process. We found that the cellular accumulation process was not modified by 24S-OH-chol treatment. Overall, our results highlight the importance of the LXR/ABCA1 system in brain pericytes and suggest a new role for these cells in brain cholesterol homeostasis.

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“…It is expressed in brain parenchymal cells [228], including the cerebrovascular endothelium [229, 230], and its brain endothelial expression levels can be pharmacologically upregulated by agonists of liver X receptors [229]. The experiments conducted in Abca1 −/− mice have shown that ABCA1 acts as a cholesterol efflux transporter at the BBB [230], but, unlike the BBB-associated low-density lipoprotein receptor-related protein 1 [231], it does not transport Aβ peptides from the brain into the blood [232]. This suggests the indirect effect of ABCA1 on Aβ deposition in the CNS.…”

Section: Tbi and The Transport Systems At The Bbbmentioning

confidence: 99%

Blood–Brain Barrier Pathophysiology in Traumatic Brain Injury

Chodobski

Zink

Szmydynger‐Chodobska

2011

Transl. Stroke Res.

540

449

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The blood-brain barrier (BBB) is formed by tightly connected cerebrovascular endothelial cells, but its normal function also depends on paracrine interactions between the brain endothelium and closely located glia. There is a growing consensus that brain injury, whether it is ischemic, hemorrhagic, or traumatic, leads to dysfunction of the BBB. Changes in BBB function observed after injury are thought to contribute to the loss of neural tissue and to affect the response to neuroprotective drugs. New discoveries suggest that considering the entire gliovascular unit, rather than the BBB alone, will expand our understanding of the cellular and molecular responses to traumatic brain injury (TBI). This review will address the BBB breakdown in TBI, the role of blood-borne factors in affecting the function of the gliovascular unit, changes in BBB permeability and post-traumatic edema formation, and the major pathophysiological factors associated with TBI that may contribute to post-traumatic dysfunction of the BBB. The key role of neuroinflammation and the possible effect of injury on transport mechanisms at the BBB will also be described. Finally, the potential role of the BBB as a target for therapeutic intervention through restoration of normal BBB function after injury and/or by harnessing the cerebrovascular endothelium to produce neurotrophic growth factors will be discussed.

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Direct evidence of abca1-mediated efflux of cholesterol at the mouse blood–brain barrier

Cited by 32 publications

References 41 publications

Bexarotene Promotes Cholesterol Efflux and Restricts Apical-to-Basolateral Transport of Amyloid-β Peptides in an In Vitro Model of the Human Blood-Brain Barrier

Bexarotene Promotes Cholesterol Efflux and Restricts Apical-to-Basolateral Transport of Amyloid-β Peptides in an In Vitro Model of the Human Blood-Brain Barrier

Brain Pericytes ABCA1 Expression Mediates Cholesterol Efflux but not Cellular Amyloid-β Peptide Accumulation

Blood–Brain Barrier Pathophysiology in Traumatic Brain Injury

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