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

J Alzheimers Dis. 2015;48(3):849-62. doi: 10.3233/JAD-150469.


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.

Keywords: ABCA1; ABCB1; Aβ peptide; RAGE; RXR; bexarotene; blood-brain barrier; cholesterol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1 / metabolism
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Anticarcinogenic Agents / pharmacology
  • Apolipoproteins E / metabolism
  • Bexarotene
  • Biological Transport / drug effects
  • Blood-Brain Barrier / drug effects*
  • Blood-Brain Barrier / metabolism*
  • Capillary Permeability / drug effects
  • Capillary Permeability / physiology
  • Cattle
  • Cholesterol / metabolism*
  • Coculture Techniques
  • Fetal Blood
  • Humans
  • Neuroprotective Agents / pharmacology*
  • Pericytes
  • Stem Cells
  • Tetrahydronaphthalenes / pharmacology*
  • Tight Junctions / drug effects
  • Tight Junctions / metabolism


  • ABCA1 protein, human
  • ABCB1 protein, human
  • ATP Binding Cassette Transporter 1
  • ATP Binding Cassette Transporter, Subfamily B
  • Amyloid beta-Peptides
  • Anticarcinogenic Agents
  • Apolipoproteins E
  • Neuroprotective Agents
  • Tetrahydronaphthalenes
  • Cholesterol
  • Bexarotene