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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 09 01; 1865(9):2224-2245.BB

Abstract

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.

Authors+Show Affiliations

Division of Immunology and Pathophysiology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria.Division of Immunology and Pathophysiology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria.Institute of Molecular Biosciences, University of Graz, Graz, Austria.Division of Immunology and Pathophysiology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria.Division of Immunology and Pathophysiology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria.Department of Cell Death and Proliferation, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), IDIBAPS, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.Department of Cell Death and Proliferation, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), IDIBAPS, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain; Department of Biomedicine, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain.Division of Immunology and Pathophysiology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria.Division of Immunology and Pathophysiology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria.Division of Immunology and Pathophysiology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria.Division of Immunology and Pathophysiology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria.Division of Immunology and Pathophysiology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria.Division of Immunology and Pathophysiology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria.Department of Cell Death and Proliferation, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), IDIBAPS, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.Institute of Molecular Biosciences, University of Graz, Graz, Austria; BioTechMed Graz, Graz, Austria.Division of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria.Division of Immunology and Pathophysiology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria. Electronic address: ute.panzenboeck@medunigraz.at.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31055081

Citation

Fanaee-Danesh, Elham, et al. "Astaxanthin Exerts Protective Effects Similar to Bexarotene in Alzheimer's Disease By Modulating Amyloid-beta and Cholesterol Homeostasis in Blood-brain Barrier Endothelial Cells." Biochimica Et Biophysica Acta. Molecular Basis of Disease, vol. 1865, no. 9, 2019, pp. 2224-2245.
Fanaee-Danesh E, Gali CC, Tadic J, et al. 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;1865(9):2224-2245.
Fanaee-Danesh, E., Gali, C. C., Tadic, J., Zandl-Lang, M., Carmen Kober, A., Agujetas, V. R., de Dios, C., Tam-Amersdorfer, C., Stracke, A., Albrecher, N. M., Manavalan, A. P. C., Reiter, M., Sun, Y., Colell, A., Madeo, F., Malle, E., & Panzenboeck, U. (2019). Astaxanthin exerts protective effects similar to bexarotene in Alzheimer's disease by modulating amyloid-beta and cholesterol homeostasis in blood-brain barrier endothelial cells. Biochimica Et Biophysica Acta. Molecular Basis of Disease, 1865(9), 2224-2245. https://doi.org/10.1016/j.bbadis.2019.04.019
Fanaee-Danesh E, et al. 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 09 1;1865(9):2224-2245. PubMed PMID: 31055081.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Astaxanthin exerts protective effects similar to bexarotene in Alzheimer's disease by modulating amyloid-beta and cholesterol homeostasis in blood-brain barrier endothelial cells. AU - Fanaee-Danesh,Elham, AU - Gali,Chaitanya Chakravarthi, AU - Tadic,Jelena, AU - Zandl-Lang,Martina, AU - Carmen Kober,Alexandra, AU - Agujetas,Vicente Roca, AU - de Dios,Cristina, AU - Tam-Amersdorfer,Carmen, AU - Stracke,Anika, AU - Albrecher,Nicole Maria, AU - Manavalan,Anil Paul Chirackal, AU - Reiter,Marielies, AU - Sun,Yidan, AU - Colell,Anna, AU - Madeo,Frank, AU - Malle,Ernst, AU - Panzenboeck,Ute, Y1 - 2019/05/02/ PY - 2018/11/20/received PY - 2019/04/28/revised PY - 2019/04/30/accepted PY - 2019/5/6/pubmed PY - 2020/5/8/medline PY - 2019/5/6/entrez KW - ABCA1 KW - APP processing KW - Alzheimer's disease KW - Blood-brain barrier KW - Cholesterol efflux KW - LRP-1 SP - 2224 EP - 2245 JF - Biochimica et biophysica acta. Molecular basis of disease JO - Biochim Biophys Acta Mol Basis Dis VL - 1865 IS - 9 N2 - 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. SN - 1879-260X UR - https://www.unboundmedicine.com/medline/citation/31055081/Astaxanthin_exerts_protective_effects_similar_to_bexarotene_in_Alzheimer's_disease_by_modulating_amyloid_beta_and_cholesterol_homeostasis_in_blood_brain_barrier_endothelial_cells_ DB - PRIME DP - Unbound Medicine ER -