The DOI matches its Crossref record; 73 of the 74 references it cites were found in a registry or an index; 4 of the 91 sources its claims cite were checked for support.
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
Open accessAbstract
One of the prime features of Alzheimer's disease (AD) is the excessive accumulation of amyloid-β (Aβ) peptides in the brain. Several recent studies suggest that this phenomenon results from the dysregulation of cholesterol homeostasis in the brain and impaired bidirectional Aβ 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 Aβ 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 Aβ peptides, bexarotene increases the expression of ABCB1, which in turn decreases Aβ 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 Aβ peptides across BBB, suggesting that bexarotene is a promising drug candidate for the treatment of AD.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
In an in vitro human blood-brain barrier model, bexarotene induced ABCA1 and increased cholesterol efflux to ApoA-I, HDL, ApoE2, and ApoE4, while upregulating ABCB1 and reducing apical-to-basolateral Aβ peptide transport. These effects occurred without changing monolayer permeability or tight junctions.
Key findings
- Bexarotene at 25–100 nM did not modify BBB permeability to Lucifer Yellow; after 100 nM bexarotene, ZO-1 and occludin junction staining remained intact with no gaps at cell borders.
- Bexarotene (100 nM) upregulated ABCA1 mRNA and protein but not SCARB1 or ApoE. Cholesterol efflux increased in the basolateral compartment by 58.8% with ApoA-I, 30.5% with HDL, 41.1% with ApoE2, and 19.8% with ApoE4, and in the apical compartment by 30.0%, 19.6%, 33.2%, and 19.7%, respectively, relative to control.
- In untreated BLECs, basolateral cholesterol efflux was 0.86% with HSA, 0.72% with ApoA-I, 2.71% with HDL, 2.25% with ApoE2, and 2.52% with ApoE4; apical efflux was 2.17%, 2.01%, 6.33%, 5.74%, and 5.37%, respectively.
- Bexarotene upregulated ABCB1 mRNA 2.45-fold and ABCB1 protein by 33%, without significant changes in RAGE (1.16-fold) or ABCC1 (1.19-fold). Apical-to-basolateral Aβ transport decreased from 1.28% to 0.96%; the ABCB1 inhibitor elacridar increased transport to 1.86%, implicating ABCB1.
Methods
- The study used an in vitro human BBB model: CD34+ hematopoietic stem cells from umbilical cord blood were differentiated into endothelial cells and co-cultured with bovine brain pericytes on Matrigel-coated Transwell inserts; after 6 days the cells were termed brain-like endothelial cells (BLECs). Treatments were 24 h with DMSO or bexarotene (0–100 nM; 100 nM for most experiments).
- Assays included endothelial permeability measurements (Lucifer Yellow, [14C]sucrose), immunostaining for ZO-1 and occludin, RT-qPCR for ABCA1, SCARB1, ApoE, ABCB1, RAGE, and ABCC1 normalized to ACTB and RPLP0, immunoblotting for ABCA1 and ABCB1, [3H]cholesterol efflux with ApoA-I, HDL, ApoE2, or ApoE4, and 30-min apical-to-basolateral transport of Cy5-Aβ(1-40) or [3H]inulin with or without 500 nM elacridar.
- Statistical analysis used one-way ANOVA followed by appropriate post hoc tests; data are reported as mean ± SD or mean ± SEM, with n = 3–12 depending on the experiment.
Limitations
- Stated in the paper: how bexarotene’s effects on cholesterol metabolism affect brain function and behavior requires further investigation; the cellular and molecular mechanisms of microglial/astrocyte-mediated Aβ clearance have not been characterized in detail; discrepancies among prior bexarotene studies may relate to altered BBB physiology in aggressive transgenic AD mouse models.
- Stated/evident from the text: findings come from an in vitro human BBB model using cord blood-derived BLECs co-cultured with bovine brain pericytes, not from in vivo human brain; transport experiments used Aβ(1-40) and 24-h treatments, so other Aβ species, chronic dosing, and behavioral outcomes are not addressed.
- Evident from the text: no in vivo validation or clinical data are reported, and no direct measurement of brain amyloid burden is performed; bexarotene did not modulate ApoE expression in this BBB model, contrasting with some other CNS cell types.
Model-written summary. Check it against the paper before relying on it.
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Cites
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Claims the paper makes
4 of 91 cited sources checked · 4 supported · 0 flagged
- Findingcitation
There were no significant differences in cholesterol efflux between the two isoforms of ApoE (ApoE2 and ApoE4) in BLECs.
“Interestingly, and as previously reported for brain pericytes [42], neurons [59], fibroblasts [60], and plexus choroid cells [61], there were no significant differences in efflux between the two isoforms of ApoE.”
Quote in the paperNot a substantial claim2 of 4 sources checked- cites [42] Saint-Pol, 2012, Brain pericytes ABCA1 expression mediates cholesterol efflux but not cellular amyloid-beta peptide accumulation, J Alzheimers Dis source
- cites [59] Kim, 2007, Role of ABCG1 and ABCA1 in regulation of neuronal cholesterol efflux to apolipoprotein E discs and suppression of amyloid-beta peptide generation, J Biol Chem source
- cites [60] Krimbou, 2004, Molecular interactions between apoEand ABCA1: Impact on apoE lipidation, J Lipid Res source
- cites [61] Fujiyoshi, 2007, 24S-hydroxycholesterol induces cholesterol release from choroid plexus epithelial cells in an apical- and apoE isoform-dependent manner concomitantly with the induction of ABCA1 and ABCG1 expression, J Neurochem source
- Findingown data
Bexarotene did not upregulate transcription of ApoE.
“Bexarotene upregulated transcription of ABCA1 (Fig. 3A) but not SCARB1 or ApoE (Fig. 3B and C, respectively).”
Quote in the paperNot a substantial claim - Findingown data
Addition of lipid-free ApoA-I particles did not significantly increase cholesterol release (0.72%).
“As we have previously observed in other brain vascular cell types [29,42], the addition of lipid-free ApoA-I particles did not significantly increase the extent of release (0.72%)”
Quote in the paperNot a substantial claim - Findingown data
The apical-to-basolateral transport of Aβ peptides was greater in the presence of elacridar than in the control condition (1.86%).
“The transport was greater in the presence of elacridar than in the control condition (1.86%).”
Quote in the paperSubstantial claim - Findingown data
After bexarotene treatment, the expression of ABCB1 was significantly upregulated by a factor of 2.45 versus the control condition.
“After bexarotene treatment, however, the expression of ABCB1 was significantly upregulated by a factor of 2.45 versus the control condition (Fig. 5A).”
Quote in the paperSubstantial claim
- Findingown data
Cholesterol release to acceptors in the basolateral compartment was significantly greater in the presence of bexarotene (increases of 58.8%, 30.5%, 41.1%, and 19.8% for ApoA-I, HDL, ApoE2, and ApoE4, respectively).
“As shown in Fig. 4A, cholesterol release to acceptors in the basolateral compartment was significantly greater in the presence of bexarotene (with respective increases of 58.8%, 30.5%, 41.1%, and 19.8% in the presence of ApoA-I, HDL, ApoE2, and ApoE4, relative to the control conditions in the absence of bexarotene).”
Quote in the paperSubstantial claim - Findingown data
Immunoblotting confirmed that ABCB1 protein expression was upregulated by 33% after bexarotene treatment.
“expression of the ABCB1 protein was upregulated by 33% (Fig. 5B).”
Quote in the paperSubstantial claim - Findingown data
Bexarotene upregulated transcription of ABCA1.
“Bexarotene upregulated transcription of ABCA1 (Fig. 3A) but not SCARB1 or ApoE (Fig. 3B and C, respectively).”
Quote in the paperSubstantial claim - Findingown data
Cholesterol release to acceptors in the apical compartment showed the same trend in the presence of bexarotene (increases of 30.0%, 19.6%, 33.2%, and 19.7% for ApoA-I, HDL, ApoE2, and ApoE4, respectively).
“Figure 4B shows the same trend in the apical compartment (with respective increases of 30.0%, 19.6%, 33.2%, and 19.7% in the presence of ApoA-I, HDL, ApoE2, and ApoE4, relative to the control conditions).”
Quote in the paperSubstantial claim - Findingown data
Addition of HDL, ApoE2, and ApoE4 increased the proportion of cholesterol release to 6.33%, 5.74%, and 5.37%, respectively.
“Addition of HDL, ApoE2, and ApoE4 increased the proportion of cholesterol release to 6.33%, 5.74%, and 5.37%, respectively.”
Quote in the paperSubstantial claim - Findingown data
Bexarotene did not significantly modify the transcriptional expression of ABCC1 (1.19-fold versus control).
“Bexarotene did not significantly modify the transcriptional expression of RAGE and ABCC1 (1.16-and 1.19-fold versus the control condition, respectively).”
Quote in the paperNot a substantial claim - Findingown data
In the absence of treatment, BLECs loaded with radioactive cholesterol effluxed a small proportion (0.86% in HSA-only control) to the basolateral medium.
“In the absence of treatment, BLECs loaded with radioactive cholesterol were able to efflux a small proportion (0.86% in an HSA-only control condition) to the basolateral medium (the brain side, Fig. 2A).”
Quote in the paperNot a substantial claim - Findingown data
ABCA1 is expressed by human BBB cells.
“Here, for the first time, we demonstrated that this transporter is also expressed by human BBB cells.”
Quote in the paperSubstantial claim - Findingown data
Intact, strong staining of junctions with no gaps at cell borders was observed in untreated and treated BLECs.
“Intact, strong staining of the junctions (with no gaps at cell borders) were observed in untreated and treated BLECs.”
Quote in the paperSubstantial claim - Findingown data
In the human BBB model, the apical-to-basolateral transport of Aβ peptides in the control condition was 1.28% after 30 min.
“In our human BBB model, the apical-to-basolateral transport of the A peptides in the control condition was 1.28% (Fig. 6) after 30 min.”
Quote in the paperSubstantial claim - Findingown data
When BLECs were treated for 24 h with bexarotene, apical-to-basolateral transport of Aβ peptides decreased by about a quarter (to 0.96%).
“When BLECs were treated for 24 h with bexarotene, this transport decreased by about a quarter (to 0.96%).”
Quote in the paperSubstantial claim - Findingown data
Bexarotene did not significantly modify the transcriptional expression of RAGE (1.16-fold versus control).
“Bexarotene did not significantly modify the transcriptional expression of RAGE and ABCC1 (1.16-and 1.19-fold versus the control condition, respectively).”
Quote in the paperNot a substantial claim - Findingown data
HDL, ApoE2, and ApoE4 increased cholesterol release by up to 3-fold compared with the HSA condition (2.71%, 2.25%, and 2.52%, respectively).
“whereas HDL, ApoE2, and ApoE4 increased release by up to 3-fold, compared with the HSA condition (2.71%, 2.25%, and 2.52%, respectively).”
Quote in the paperSubstantial claim - Findingown data
Bexarotene did not upregulate transcription of SCARB1.
“Bexarotene upregulated transcription of ABCA1 (Fig. 3A) but not SCARB1 or ApoE (Fig. 3B and C, respectively).”
Quote in the paperNot a substantial claim - Findingown data
Cholesterol efflux from BLECs is preferentially directed to the apical compartment (the blood side).
“The cholesterol efflux is preferentially directed to the apical compartment (the blood side) and probably helps regulating the cerebral pool of cholesterol.”
Quote in the paperSubstantial claim - Findingown data
At concentrations of 25 to 100 nM, bexarotene did not modify the monolayer's permeability to LY.
“At concentrations of 25 to 100 nM, bexarotene did not modify the monolayer's permeability (Pe) to the [28,39,73].”
Quote in the paperSubstantial claim - Findingown data
Neither bexarotene nor elacridar significantly affected the apical-to-basolateral transport of inulin.
“Neither bexarotene nor elacridar significantly affected the apical-to-basolateral transport of inulin (data not shown).”
Quote in the paperNot a substantial claim - Findingown data
Bexarotene-mediated upregulation of ABCA1 in BLECs is correlated with an increase in cholesterol efflux to ApoA-I, HDL, ApoE2, and ApoE4 particles.
“Furthermore, our data showed that bexarotene-mediated upregulation of ABCA1 in BLECs is correlated with an increase in cholesterol efflux to ApoA-I, HDL, ApoE2, and ApoE4 particles.”
Quote in the paperSubstantial claim - Findingown data
Elacridar at 500 nM did not modify the monolayer's permeability to [14C]sucrose.
“At a concentration of 500 nM, elacridar did not modify the monolayer's permeability to 14 [C]sucrose (data not shown).”
Quote in the paperSubstantial claim - Findingown data
Treatment with bexarotene provoked upregulation of the ABCB1 transporter.
“Our results showed that treatment with bexarotene provoked upregulation of the ABCB1 transporter and thus a decrease in A peptide entry into the brain compartment.”
Quote in the paperSubstantial claim - Findingown data
The influx of soluble forms of Aβ peptide across BLECs (in the apical-to-basolateral direction) is decreased by bexarotene.
“and the influx of soluble forms of A peptide across BLECs (in the apical-to-basolateral direction) is decreased”
Quote in the paperSubstantial claim - Findingown data
The bexarotene-induced decrease in apical-to-basolateral Aβ peptide transport across the BBB is ABCB1-mediated.
“The results of our experiments with the specific ABCB1 inhibitor elacridar [34,45] definitively confirmed that the process was ABCB1-mediated, since the compound restored apical-to-basolateral A peptide transport across the BBB.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [34] Candela, 2010, Apical-to-basolateral transport of amyloid-beta peptides through blood-brain barrier cells is mediated by the receptor for advanced glycation end-products and is restricted by P-glycoprotein, J Alzheimers Dis source
- cites [45] Tai, 2009, P-glycoprotein and breast cancer resistance protein restrict apical-to-basolateral permeability of human brain endothelium to amyloid-beta, J Cereb Blood Flow Metab source
- Findingown data
Treatment with bexarotene decreased Aβ peptide entry into the brain compartment.
“Our results showed that treatment with bexarotene provoked upregulation of the ABCB1 transporter and thus a decrease in A peptide entry into the brain compartment.”
Quote in the paperSubstantial claim - Findingown data
Bexarotene does not modulate the expression of ApoE by BLECs.
“Interestingly, we also observed that bexarotene did not modulate the expression of ApoE by BLECs.”
Quote in the paperNot a substantial claim - Interpretationown data
Bexarotene's upregulation of ABCB1 decreases apical-to-basolateral transport of Aβ peptides.
“Our results demonstrate that bexarotene (1) induces the expression of ABCA1, (2) mediates the efflux of cholesterol toward ApoA-I, ApoE2, ApoE4, and HDL, and (3) increases the expression of ABCB1, which in turn decreases the apical-to-basolateral transport of A peptides.”
Quote in the paperSubstantial claim - Interpretationreasoning
Bexarotene's effects cannot be observed in models in which the BBB's physiology and integrity are modified.
“However, these effects cannot be observed in models in which the BBB's physiology and integrity are modified.”
Quote in the paperSubstantial claim - Premisecitation
Membrane cholesterol content influences ABCA1 activity.
“Because membrane cholesterol content influences also the ABCA1 activity [58]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [58] Takahashi, 2006, Purification and ATPase activity of human ABCA1, J Biol Chem source
- Interpretationreasoning
Bexarotene likely modulates ABCA1 activity.
“it is likely that bexarotene also modulates the ABCA1 activity.”
Quote in the paperSubstantial claim - Premisecitation
Genetic modifications altering amyloid synthesis can alter the physiological properties of the BBB in murine models of Alzheimer's disease, often before the onset of disease.
“Indeed, several studies have highlighted that genetic modifications altering the amyloid synthesis can alter the physiological properties of the BBB in these models-often before the onset of the disease itself.”
Quote in the paperSubstantial claim - Premisecitation
Knock-out of ABCA1 provokes an accumulation of Aβ peptide in the CNS.
“knock-out of this gene provokes an accumulation of A peptide in the CNS [12,13,56].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [12] Hirsch-Reinshagen, 2005, The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease, J Biol Chem source
- cites [13] Wahrle, 2005, Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease, J Biol Chem source
- cites [56] Fitz, 2012, Abca1 deficiency affects Alzheimer’s disease-like phenotype in human ApoE4 but not in ApoE3-targeted replacement mice, J Neurosci source
- Premisecitation
In the brain, ApoE's lipidation status depends on ABCA1, which transfers lipids to ApoE, ApoA-I, and HDLs.
“In the brain, ApoE's lipidation status depends on the ATP-binding cassette family subfamily A member 1 transporter (ABCA1), which transfers lipids to ApoE, ApoA-I, and high-density lipoproteins (HDLs) [9,10].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [9] Hirsch-Reinshagen, 2007, Cholesterol metabolism, apolipoprotein E, adenosine triphosphate-binding cassette transporters, and Alzheimer’s disease, Curr Opin Lipidol source
- cites [10] Koldamova, 2010, The role of ATP-binding cassette transporter A1 in Alzheimer’s disease and neurodegeneration, Biochim Biophys Acta source
- Premisecitation
ABCA1's impact on brain cholesterol metabolism modulates the brain's amyloid burden.
“This transporter is of prime interest in AD because its impact on brain cholesterol metabolism modulates the brain's amyloid burden.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [14] Wahrle, 2008, Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease, J Clin Invest source
- cites [12] Hirsch-Reinshagen, 2005, The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease, J Biol Chem source
- cites [13] Wahrle, 2005, Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease, J Biol Chem source
- cites [56] Fitz, 2012, Abca1 deficiency affects Alzheimer’s disease-like phenotype in human ApoE4 but not in ApoE3-targeted replacement mice, J Neurosci source
- Premisecitation
Oral administration of bexarotene increased clearance of Aβ peptides in AD mice.
“In 2012, Cramer et al. elegantly demonstrated that oral administration of this molecule decreased the area and number of A plaques, increased the clearance of A peptides, stimulated memory (contextual fear conditioning) and olfactory functions, and improved the social behavior (construction nest) of treated AD mice [17].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Cramer, 2012, ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models, Science source
- Interpretationown data
The human BBB is involved in cholesterol homeostasis in the brain and the periphery.
“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].”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [29] Saint-Pol, 2013, Oxysterols decrease apical-to-basolateral transport of Aβ peptides via an ABCB1-mediated process in an in vitro blood-brain barrier model constituted of bovine brain capillary endothelial cells, Brain Res source
- cites [31] Do, 2011, Direct evidence of abca1-mediated efflux of cholesterol at the mouse blood-brain barrier, Mol Cell Biochem source
- cites [42] Saint-Pol, 2012, Brain pericytes ABCA1 expression mediates cholesterol efflux but not cellular amyloid-beta peptide accumulation, J Alzheimers Dis source
- cites [62] Karasinska, 2009, Specific loss of brain ABCA1 increases brain cholesterol uptake and influences neuronal structure and function, J Neurosci source
- Premisecitation
ABCA1 is the major protagonist in the exchange of cholesterol between the brain and the blood.
“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].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [29] Saint-Pol, 2013, Oxysterols decrease apical-to-basolateral transport of Aβ peptides via an ABCB1-mediated process in an in vitro blood-brain barrier model constituted of bovine brain capillary endothelial cells, Brain Res source
- cites [30] Panzenboeck, 2002, ABCA1 and scavenger receptor class B, type I, are modulators of reverse sterol transport at an in vitro blood-brain barrier constituted of porcine brain capillary endothelial cells, J Biol Chem source
- cites [31] Do, 2011, Direct evidence of abca1-mediated efflux of cholesterol at the mouse blood-brain barrier, Mol Cell Biochem source
- Premisecitation
Deletion of ABCA1 expression increases amyloid burden in murine models of Alzheimer's disease.
“Several studies have demonstrated that deletion of ABCA1 expression increases the amyloid burden in murine models of AD [11][12][13]”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [11] Koldamova, 2005, Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice, J Biol Chem source
- cites [12] Hirsch-Reinshagen, 2005, The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease, J Biol Chem source
- cites [13] Wahrle, 2005, Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease, J Biol Chem source
- Premisecitation
Oral administration of bexarotene improved social behavior of treated AD mice.
“In 2012, Cramer et al. elegantly demonstrated that oral administration of this molecule decreased the area and number of A plaques, increased the clearance of A peptides, stimulated memory (contextual fear conditioning) and olfactory functions, and improved the social behavior (construction nest) of treated AD mice [17].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [17] Cramer, 2012, ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models, Science source
- Study design and conductown data
The in vitro model of the human BBB expresses RXRs.
“By using an in vitro model of the human BBB that expresses the RXRs (the cells' gene expression profile is available at http://www.ncbi. nlm.nih.gov/geo/query/acc.cgi?acc=GSE45171)”
Quote in the paperSubstantial claim - Interpretationreasoning
Cholesterol efflux from BLECs probably helps regulate the cerebral pool of cholesterol.
“The cholesterol efflux is preferentially directed to the apical compartment (the blood side) and probably helps regulating the cerebral pool of cholesterol.”
Quote in the paperSubstantial claim - Interpretationreasoning
Bexarotene can act at the BBB to decrease the amyloid burden in AD patients and animal models.
“In conclusion, our present results add to the growing body of evidence to show that bexarotene can act at the BBB to decrease the amyloid burden in AD patients and animal models.”
Quote in the paperSubstantial claim - Interpretationreasoning
Bexarotene acts directly at the BBB by modulating the transport of Aβ peptides.
“Secondly, bexarotene acts directly at the BBB by modulating the transport of A peptides.”
Quote in the paperSubstantial claim - Interpretationreasoning
Bexarotene can act on AD at several levels.
“In summary, our present observations suggest that bexarotene can act on AD at several levels.”
Quote in the paperSubstantial claim - Interpretationreasoning
Bexarotene modifies the brain's cholesterol metabolism via an ABCA1- and ApoE-dependent process.
“Firstly, bexarotene modifies the brain's cholesterol metabolism via an ABCA1-and ApoE-dependent process.”
Quote in the paperSubstantial claim - Premisecitation
RAGE is exclusively expressed at the apical side of brain ECs.
“RAGE is exclusively expressed at the apical side of the brain ECs and mediates the entry of the A peptide into the brain via a caveola-mediated process [32].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [32] Deane, 2003, RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain, Nat Med source
- Premisecitation
The brain efflux of Aβ peptide across the BBB is increased by bexarotene.
“The brain efflux of A peptide across the BBB is increased [65]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [65] Bachmeier, 2013, Stimulation of the retinoid X receptor facilitates beta-amyloid clearance across the blood-brain barrier, J Mol Neurosci source
- Premisecitation
ABCB1 is involved in Aβ peptide transport across the BBB.
“but it is now clear that ABCB1 is also involved in A peptide transport across the BBB.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [37] Krohn, 2011, Cerebral amyloid-beta proteostasis is regulated by the membrane transport protein ABCC1 in mice, J Clin Invest source
- cites [67] Cirrito, 2005, P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model, J Clin Invest source
- cites [34] Candela, 2010, Apical-to-basolateral transport of amyloid-beta peptides through blood-brain barrier cells is mediated by the receptor for advanced glycation end-products and is restricted by P-glycoprotein, J Alzheimers Dis source
- cites [45] Tai, 2009, P-glycoprotein and breast cancer resistance protein restrict apical-to-basolateral permeability of human brain endothelium to amyloid-beta, J Cereb Blood Flow Metab source
- Interpretationreasoning
Bexarotene might upregulate ABCB1 expression via the formation of RXR/LXR heterodimers.
“Therefore, bexarotene might upregulate ABCB1 expression via the formation of RXR/LXR heterodimers; this would be a very attractive therapeutic approach for AD [72].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [72] Koldamova, 2007, Role of LXR and ABCA1 in the pathogenesis of Alzheimer’s disease - implications for a new therapeutic approach, Curr Alzheimer Res source
- Premisecitation
RAGE mediates the entry of Aβ peptide into the brain.
“RAGE is exclusively expressed at the apical side of the brain ECs and mediates the entry of the A peptide into the brain via a caveola-mediated process [32].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [32] Deane, 2003, RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain, Nat Med source
- Probably not a substantial claim. 21
- It may state two separate claims as one. 15
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationSome studies have reported a role for ABCB1 in Aβ peptide elimination from the brain.
“Whereas some studies have reported a role for ABCB1 in A peptide elimination from the brain [37,67]”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [37] Krohn, 2011, Cerebral amyloid-beta proteostasis is regulated by the membrane transport protein ABCC1 in mice, J Clin Invest source
- cites [67] Cirrito, 2005, P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model, J Clin Invest source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Findingown dataThese results were correlated with levels of protein expression.
“These results were correlated with levels of protein expression (Fig. 3D).”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Findingown dataThe Pe values were correlated with immunohistochemical labeling of tight junction proteins ZO-1 and occludin.
“The Pe values were correlated with immunohistochemical labeling of the tight junction protein ZO-1 and occludin (Fig. 1B).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataIn the apical medium, the proportions of cholesterol efflux in HSA and ApoA-I conditions were 2.17% and 2.01%, respectively.
“In the apical (bloodside) medium, the proportions of cholesterol efflux in the HSA-and in the ApoA-I particle-conditions were 2.17% and 2.01%, respectively (Fig. 2B).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataThe expression of ABCC1 and RAGE was not modified by bexarotene treatment.
“The expression of ABCC1 and RAGE was not modified by the treatment.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationRAGE is involved in the blood-to-brain transport of Aβ.
“The receptor for advanced glycation end-products (RAGE, expressed at the EC luminal membrane) is involved in the blood-tobrain transport of A [32,34]”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [32] Deane, 2003, RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain, Nat Med source
- cites [34] Candela, 2010, Apical-to-basolateral transport of amyloid-beta peptides through blood-brain barrier cells is mediated by the receptor for advanced glycation end-products and is restricted by P-glycoprotein, J Alzheimers Dis source
Probably not a substantial claim.
PremisecitationAccumulation of amyloid-β peptides in the brain is one of the prime features of Alzheimer's disease.
“According to the amyloid cascade hypothesis, accumulation of amyloid- (A) peptides in the brain is one of the prime features of AD [1].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Hardy, 1992, Alzheimer’s disease: The amyloid cascade hypothesis, Science source
It may state two separate claims as one.
PremisecitationOral administration of bexarotene stimulated memory and olfactory functions in AD mice.
“In 2012, Cramer et al. elegantly demonstrated that oral administration of this molecule decreased the area and number of A plaques, increased the clearance of A peptides, stimulated memory (contextual fear conditioning) and olfactory functions, and improved the social behavior (construction nest) of treated AD mice [17].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [17] Cramer, 2012, ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models, Science source
It may state two separate claims as one.
PremisecitationThe BBB participates in the regulation of the brain pool of Aβ peptides and the re-entry of these peptides into the brain.
“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].”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [32] Deane, 2003, RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain, Nat Med source
- cites [33] Deane, 2012, A multimodal RAGE-specific inhibitor reduces amyloid beta-mediated brain disorder in a mouse model of Alzheimer disease, J Clin Invest source
- cites [34] Candela, 2010, Apical-to-basolateral transport of amyloid-beta peptides through blood-brain barrier cells is mediated by the receptor for advanced glycation end-products and is restricted by P-glycoprotein, J Alzheimers Dis source
- cites [35] Eisele, 2010, Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis, Science source
- cites [36] Sutcliffe, 2011, Peripheral reduction of beta-amyloid is sufficient to reduce brain beta-amyloid: Implications for Alzheimer’s disease, J Neurosci Res source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationSeveral research groups have tried to reproduce Cramer's initial study in various AD models, with disparate results.
“Several research groups have tried to reproduce Cramer's initial study in various different AD models, with disparate results [18][19][20][21][22][23].”
Quote in the paperNot a substantial claim0 of 6 sources checked- cites [18] Fitz, 2013, Comment on “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models”, Science source
- cites [19] LaClair, 2013, Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice, Mol Neurodegener source
- cites [20] Price, 2013, Comment on “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models”, Science source
- cites [21] Tesseur, 2013, Comment on “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models”, Science source
- cites [22] Ulrich, 2013, In vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis, Mol Neurodegener source
- cites [23] Veeraraghavalu, 2013, Comment on “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models”, Science source
It may state two separate claims as one.
PremisecitationAfter 6 days of co-culture, ECs acquire tight junctions and transporters typically observed in brain endothelium and display most of the BBB's in vivo properties for at least 20 days.
“After 6 days of co-culture, the ECs acquire the tight junctions and transporters typically observed in brain endothelium and display most of the BBB's in vivo properties for at least 20 days [39].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [39] Cecchelli, 2014, A stable and reproducible human blood-brain barrier model derived from hematopoietic stem cells, PLoS One source
It may state two separate claims as one.
PremisecitationOral administration of bexarotene decreased the area and number of Aβ plaques in AD mice.
“In 2012, Cramer et al. elegantly demonstrated that oral administration of this molecule decreased the area and number of A plaques, increased the clearance of A peptides, stimulated memory (contextual fear conditioning) and olfactory functions, and improved the social behavior (construction nest) of treated AD mice [17].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Cramer, 2012, ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models, Science source
Probably not a substantial claim. It may state two separate claims as one.
PremisecitationOverexpression of ABCA1 decreases amyloid deposition and improves animals' behavior.
“whereas overexpression of the gene decreases amyloid deposition and improves the animals' behavior [14].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] Wahrle, 2008, Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease, J Clin Invest source
Probably not a substantial claim.
PremisecitationDysregulation of brain cholesterol metabolism and Aβ peptide transport across the BBB are thought to have a key role in Alzheimer's disease.
“Dysregulation of brain cholesterol metabolism and A peptide transport across the BBB are thought to have a key role in the development of AD [25,47].”
Quote in the paperSubstantial claim0 of 2 sources checkedIt may state two separate claims as one.
PremisecitationBexarotene is an RXR agonist that modulates the expression of ABCA1 and ApoE.
“treating AD is the administration of bexarotene [24,48,49], an RXR agonist that modulates the expression of ABCA1 and ApoE (both of which are major proteins regulating cholesterol homeostasis in the brain and periphery).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [24] Tousi, 2015, The emerging role of bexarotene in the treatment of Alzheimer’s disease: Current evidence, Neuropsychiatr Dis Treat source
- cites [48] Boehm-Cagan, 2014, Reversal of apoE4-driven brain pathology and behavioral deficits by bexarotene, J Neurosci source
- cites [49] Lalloyer, 2006, The RXR agonist bexarotene improves cholesterol homeostasis and inhibits atherosclerosis progression in a mouse model of mixed dyslipidemia, Arterioscler Thromb Vasc Biol source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationOverexpression of ABCA1 decreases amyloid accumulation.
“Whereas overexpression of ABCA1 decreases the amyloid accumulation [14]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [14] Wahrle, 2008, Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease, J Clin Invest source
Probably not a substantial claim. It may state two separate claims as one.
PremisecitationABCB1 and probably ABCC1 restrict Aβ re-entry into the brain.
“whereas ABCB1 and probably ABCC1 restrict A re-entry into the brain [25,37,38].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [25] Gosselet, 2013, Amyloid-beta peptides, Alzheimer’s disease and the blood-brain barrier, Curr Alzheimer Res source
- cites [37] Krohn, 2011, Cerebral amyloid-beta proteostasis is regulated by the membrane transport protein ABCC1 in mice, J Clin Invest source
- cites [38] Krohn, 2015, Accumulation of murine amyloid-beta mimics early Alzheimer’s disease, Brain source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationABCA1 is expressed by brain microvessel ECs from animals.
“It has previously been reported that ABCA1 is expressed by brain microvessel ECs from animals [29,30,57].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [29] Saint-Pol, 2013, Oxysterols decrease apical-to-basolateral transport of Aβ peptides via an ABCB1-mediated process in an in vitro blood-brain barrier model constituted of bovine brain capillary endothelial cells, Brain Res source
- cites [30] Panzenboeck, 2002, ABCA1 and scavenger receptor class B, type I, are modulators of reverse sterol transport at an in vitro blood-brain barrier constituted of porcine brain capillary endothelial cells, J Biol Chem source
- cites [57] Akanuma, 2008, Expression of nuclear receptor mRNA and liver X receptor-mediated regulation of ABC transporter A1 at rat blood-brain barrier, Neurochem Int source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationBexarotene induces microglial and astrocyte-mediated clearance of Aβ peptides.
“Furthermore, bexarotene induces microglial and astrocyte-mediated clearance of A peptides, although the corresponding cellular and molecular mechanisms have yet to be characterized in detail [17].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [17] Cramer, 2012, ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models, Science source
It may state two separate claims as one.
PremisecitationBBB integrity and brain vascular volume and expression of receptors and transporters are rapidly altered in murine models of Alzheimer's disease.
“For example, the BBB's integrity [52,53] and the brain's vascular volume and expression of receptors and transporters [54,55] are rapidly altered in murine models of AD.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [52] Ujiie, 2003, Blood-brain barrier permeability precedes senile plaque formation in an Alzheimer disease model, Microcirculation source
- cites [53] Paul, 2007, Fibrin deposition accelerates neurovascular damage and neuroinflammation in mouse models of Alzheimer’s disease, J Exp Med source
- cites [54] Do, 2014, Altered cerebral vascular volumes and solute transport at the blood-brain barriers of two transgenic mouse models of Alzheimer’s disease, Neuropharmacology source
- cites [55] Bourasset, 2009, Reduction of the cerebrovascular volume in a transgenic mouse model of Alzheimer’s disease, Neuropharmacology source
It may state two separate claims as one.
InterpretationreasoningThe bexarotene-induced decrease in Aβ influx could reduce Aβ re-entry into the brain and thus limit further accumulation within this compartment.
“this could reduce A re-entry into the brain and thus limit further accumulation within this compartment.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationABCC1 mediates Aβ peptide transport across the BBB.
“More recently, it has been suggested that ABCC1 (another efflux pump expressed by BBB cells) mediates A peptide transport across the BBB [37].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] Krohn, 2011, Cerebral amyloid-beta proteostasis is regulated by the membrane transport protein ABCC1 in mice, J Clin Invest source
Probably not a substantial claim.
PremisecitationThe expression of ABCB1 is regulated by the liver X receptor (LXR) partner.
“Previous studies have reported that the expression of this transporter is regulated by the liver X receptor (LXR) partner [47,71].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [47] Gosselet, 2014, Effects of oxysterols on the blood-brain barrier: Implications for Alzheimer’s disease, Biochem Biophys Res Commun source
- cites [71] ElAli, 2012, Liver X receptor activation enhances blood-brain barrier integrity in the ischemic brain and increases the abundance of ATP-binding cassette transporters ABCB1 and ABCC1 on brain capillary cells, Brain Pathol source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationThe levels of ApoE and HDL (or HDL-like particles) are important parameters for the cholesterol shuttle between neurons and astrocytes and for the BBB-mediated clearance of Aβ peptides.
“The levels of ApoE and HDL (or HDL-like particles) are important parameters for the cholesterol shuttle between neurons and astrocytes and for the BBBmediated clearance of A peptides [9,25,47].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [9] Hirsch-Reinshagen, 2007, Cholesterol metabolism, apolipoprotein E, adenosine triphosphate-binding cassette transporters, and Alzheimer’s disease, Curr Opin Lipidol source
- cites [25] Gosselet, 2013, Amyloid-beta peptides, Alzheimer’s disease and the blood-brain barrier, Curr Alzheimer Res source
- cites [47] Gosselet, 2014, Effects of oxysterols on the blood-brain barrier: Implications for Alzheimer’s disease, Biochem Biophys Res Commun source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationOther studies have demonstrated that ABCB1 restricts the re-entry of Aβ peptides into the CNS.
“others have demonstrated that this transporter restricts the re-entry of these peptides into the CNS [34,45].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [34] Candela, 2010, Apical-to-basolateral transport of amyloid-beta peptides through blood-brain barrier cells is mediated by the receptor for advanced glycation end-products and is restricted by P-glycoprotein, J Alzheimers Dis source
- cites [45] Tai, 2009, P-glycoprotein and breast cancer resistance protein restrict apical-to-basolateral permeability of human brain endothelium to amyloid-beta, J Cereb Blood Flow Metab source
Probably not a substantial claim.
PremisecitationABCB1's function and expression are closely linked to the lipid composition of cell membranes and the cellular cholesterol content.
“It is now acknowledged that ABCB1's function and expression are closely linked to the lipid composition of cell membranes and the cellular cholesterol content [69,70].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [69] Troost, 2004, Cholesterol modulates P-glycoprotein activity in human peripheral blood mononuclear cells, Biochem Biophys Res Commun source
- cites [70] Celestino, 2015, ABCB1, ABCC1, and LRP gene expressions are altered by LDL, HDL, and serum deprivation in a human doxorubicin-resistant uterine sarcoma cell line, Biochem Biophys Res Commun source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationBexarotene does not induce the expression of ApoE in hippocampal neurons.
“but not in hippocampal neurons [48].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [48] Boehm-Cagan, 2014, Reversal of apoE4-driven brain pathology and behavioral deficits by bexarotene, J Neurosci source
It may state two separate claims as one.
PremisecitationRAGE and ABCB1 play a role in the re-entry of Aβ peptides into the CNS.
“Given that we have previously characterized the role of RAGE and ABCB1 in the re-entry of A peptides into the CNS [29,34,42]”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [29] Saint-Pol, 2013, Oxysterols decrease apical-to-basolateral transport of Aβ peptides via an ABCB1-mediated process in an in vitro blood-brain barrier model constituted of bovine brain capillary endothelial cells, Brain Res source
- cites [34] Candela, 2010, Apical-to-basolateral transport of amyloid-beta peptides through blood-brain barrier cells is mediated by the receptor for advanced glycation end-products and is restricted by P-glycoprotein, J Alzheimers Dis source
- cites [42] Saint-Pol, 2012, Brain pericytes ABCA1 expression mediates cholesterol efflux but not cellular amyloid-beta peptide accumulation, J Alzheimers Dis source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationBexarotene can promote the brain-to-blood transport of Aβ peptides in vitro and in vivo in the presence of ApoE.
“For example, previous research has demonstrated that bexarotene can promote the brain-to-blood transport of A peptides in vitro and in vivo in the presence of ApoE [65].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [65] Bachmeier, 2013, Stimulation of the retinoid X receptor facilitates beta-amyloid clearance across the blood-brain barrier, J Mol Neurosci source
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
InterpretationreasoningIt is likely that bexarotene-induced modifications also impact Aβ peptide synthesis and macrophage-mediated Aβ clearance.
“but it is likely that these modifications also impact A peptide synthesis and macrophage-mediated A clearance.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationBexarotene induces the expression of ApoE in several CNS cell types and in brain extracts.
“Bexarotene has been shown to induce the expression of ApoE in several CNS cell types and in brain extracts [17,63,64]”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [17] Cramer, 2012, ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models, Science source
- cites [63] Xu, 2015, Bexarotene reduces blood-brain barrier permeability in cerebral ischemia-reperfusion injured rats, PLoS One source
- cites [64] Zhao, 2014, Retinoic acid isomers facilitate apolipoprotein E production and lipidation in astrocytes through the retinoid X receptor/retinoic acid receptor pathway, J Biol Chem source
The paper relies on this without support.
Bexarotene crosses the blood-brain barrier.
“Given that (1) bexarotene crosses the BBB and (2) BLECs express nuclear RXR, we next assessed the drug's influence on cholesterol exchange in the apical and basolateral compartments.”
The paper relies on this without support.
The bexarotene concentrations used (25-100 nM) are not toxic to BLECs.
“In vitro, we used the same bexarotene concentrations used in the literature.These were not toxic and did not modify the permeability of the BBB in our culture system.”
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Metadata
- Authors
- Kuntz, M., Candela, P., Saint-Pol, J., Lamartinière, Y., Boucau, M.-C., Sevin, E., Fenart, L., & Gosselet, F.
- Affiliations
- Université d'Artois (FR)
- Corresponding author
- Gosselet, Fabien
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2015-10-01
- Volume
- 48
- Issue
- 3
- Pages
- 849-862
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W1931867099
- Cited by
- 55
- References
- 74
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 6 · 2022: 3 · 2021: 8 · 2020: 7 · 2019: 7 · 2018: 7 · 2017: 4 · 2016: 8
- FWCI
- 3.04
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Alzheimer s Disease (publishedVersion, other-oa)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by-nc)
- Funders
- Ministère de l'Education Nationale, de l'Enseignement Superieur et de la Recherche
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- bexarotene, amyloid-beta
- MeSH terms
- Bexarotene, Animals, Apolipoproteins E, Biological Transport, Blood-Brain Barrier, Capillary Permeability, Cattle, Cholesterol, Fetal Blood, Humans, Stem Cells, Tetrahydronaphthalenes, Amyloid beta-Peptides, Anticarcinogenic Agents, ATP Binding Cassette Transporter, Subfamily B, Neuroprotective Agents, Coculture Techniques, Tight Junctions, Pericytes, ATP Binding Cassette Transporter 1
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