Astaxanthin exerts protective effects similar to bexarotene in Alzheimer's disease by modulating amyloid-beta and cholesterol homeostasis in blood-brain barrier endothelial cells

Biochim Biophys Acta Mol Basis Dis. 2019 Sep 1;1865(9):2224-2245. doi: 10.1016/j.bbadis.2019.04.019. Epub 2019 May 2.


The pathogenesis of Alzheimer's disease (AD) is characterized by overproduction, impaired clearance, and deposition of amyloid-β peptides (Aβ) and connected to cholesterol homeostasis. Since the blood-brain barrier (BBB) is involved in these processes, we investigated effects of the retinoid X receptor agonist, bexarotene (Bex), and the peroxisome proliferator-activated receptor α agonist and antioxidant, astaxanthin (Asx), on pathways of cellular cholesterol metabolism, amyloid precursor protein processing/Aβ production and transfer at the BBB in vitro using primary porcine brain capillary endothelial cells (pBCEC), and in 3xTg AD mice. Asx/Bex downregulated transcription/activity of amyloidogenic BACE1 and reduced Aβ oligomers and ~80 kDa intracellular 6E10-reactive APP/Aβ species, while upregulating non-amyloidogenic ADAM10 and soluble (s)APPα production in pBCEC. Asx/Bex enhanced Aβ clearance to the apical/plasma compartment of the in vitro BBB model. Asx/Bex increased expression levels of ABCA1, LRP1, and/or APOA-I. Asx/Bex promoted cholesterol efflux, partly via PPARα/RXR activation, while cholesterol biosynthesis/esterification was suppressed. Silencing of LRP-1 or inhibition of ABCA1 by probucol reversed Asx/Bex-mediated effects on levels of APP/Aβ species in pBCEC. Murine (m)BCEC isolated from 3xTg AD mice treated with Bex revealed elevated expression of APOE and ABCA1. Asx/Bex reduced BACE1 and increased LRP-1 expression in mBCEC from 3xTg AD mice when compared to vehicle-treated or non-Tg treated mice. In parallel, Asx/Bex reduced levels of Aβ oligomers in mBCEC and Aβ species in brain soluble and insoluble fractions of 3xTg AD mice. Our results suggest that both agonists exert beneficial effects at the BBB by balancing cholesterol homeostasis and enhancing clearance of Aβ from cerebrovascular endothelial cells.

Keywords: ABCA1; APP processing; Alzheimer's disease; Blood-brain barrier; Cholesterol efflux; LRP-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM10 Protein / metabolism
  • ATP Binding Cassette Transporter 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter 1 / metabolism
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Apolipoproteins E / metabolism
  • Bexarotene / pharmacology*
  • Bexarotene / therapeutic use
  • Blood-Brain Barrier / drug effects*
  • Blood-Brain Barrier / metabolism
  • Cholesterol / metabolism*
  • Down-Regulation / drug effects
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism
  • Female
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Probucol / pharmacology
  • Protective Agents / pharmacology*
  • Swine
  • Xanthophylls / pharmacology


  • ATP Binding Cassette Transporter 1
  • Amyloid beta-Peptides
  • Apolipoproteins E
  • Protective Agents
  • Xanthophylls
  • astaxanthine
  • Cholesterol
  • Bexarotene
  • Amyloid Precursor Protein Secretases
  • ADAM10 Protein
  • Probucol