Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice

Mol Neurodegener. 2013 Jun 13;8:18. doi: 10.1186/1750-1326-8-18.

Abstract

Background: Though the precise cause(s) of Alzheimer's disease (AD) remain unknown, there is strong evidence that decreased clearance of β-amyloid (Aβ) from the brain can contribute to the disease. Therapeutic strategies to promote natural Aβ clearance mechanisms, such as the protein apolipoprotein-E (APOE), hold promise for the treatment of AD. The amount of APOE in the brain is regulated by nuclear receptors including retinoid X receptors (RXRs). Drugs that activate RXRs, including bexarotene, can increase APOE and ABCA1 production, and have been shown to decrease the Aβ burden and improve cognition in mouse models of Aβ amyloidosis. Although recent bexarotene studies failed to replicate the rapid clearance of Aβ from brains, behavioral and cognitive effects of this compound remain controversial.

Findings: In efforts to clarify these behavioral findings, mutant APP/PS1 mice were acutely dosed with bexarotene. While ABCA1 was upregulated in mutant APP/PS1 mice treated with bexarotene, this drug failed to attenuate Aβ plaques or cognitive deficits in these mice.

Conclusions: We recommend rigorous preclinical study to evaluate the mechanism and utility of such a compound for AD therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1
  • ATP-Binding Cassette Transporters / biosynthesis*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology*
  • Animals
  • Anticarcinogenic Agents / pharmacology*
  • Apolipoproteins E / biosynthesis
  • Behavior, Animal / drug effects
  • Bexarotene
  • Blotting, Western
  • Disease Models, Animal
  • Female
  • Male
  • Memory / drug effects
  • Mice
  • Mice, Mutant Strains
  • Plaque, Amyloid / metabolism
  • Plaque, Amyloid / pathology*
  • Tetrahydronaphthalenes / pharmacology*

Substances

  • ATP Binding Cassette Transporter 1
  • ATP-Binding Cassette Transporters
  • Anticarcinogenic Agents
  • Apolipoproteins E
  • Tetrahydronaphthalenes
  • Bexarotene