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
| Autor: | Marie-Christine Boucau, Laurence Fenart, Yordenca Lamartiniere, Julien Saint-Pol, Emmanuel Sevin, Pietra Candela, Mélanie Kuntz, Fabien Gosselet |
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| Přispěvatelé: | Laboratoire de Physiopathologie de la Barrière Hémato-Encéphalique (LBHE), Université d'Artois (UA) |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Apolipoprotein E
[SDV]Life Sciences [q-bio] ABCA1 Pharmacology 0302 clinical medicine Bexarotene 0303 health sciences Stem Cells General Neuroscience ABCB1 General Medicine Fetal Blood RAGE 3. Good health Psychiatry and Mental health Clinical Psychology Neuroprotective Agents medicine.anatomical_structure lipids (amino acids peptides and proteins) medicine.symptom ATP Binding Cassette Transporter 1 medicine.drug Agonist ATP Binding Cassette Transporter Subfamily B Tetrahydronaphthalenes medicine.drug_class RXR Biology Retinoid X receptor Blood–brain barrier Tight Junctions Capillary Permeability 03 medical and health sciences Apolipoproteins E Downregulation and upregulation Aβ peptide medicine Animals Anticarcinogenic Agents Humans 030304 developmental biology Amyloid beta-Peptides bexarotene cholesterol Biological Transport blood-brain barrier Coculture Techniques Mechanism of action biology.protein Cattle Geriatrics and Gerontology Pericytes 030217 neurology & neurosurgery |
| Zdroj: | Journal of Alzheimer's Disease Journal of Alzheimer's Disease, IOS Press, 2015, 48 (3), pp.849-862. ⟨10.3233/JAD-150469⟩ |
| ISSN: | 1387-2877 |
| DOI: | 10.3233/JAD-150469⟩ |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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