Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Fanaee Danesh, E.
Bexarotene and astaxanthin modulate cholesterol and amyloid-beta metabolism at the blood-brain barrier
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2019. pp. 149
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Graier Wolfgang
- Panzenboeck Ute
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- Abstract:
- Background: Alzheimer's disease (AD) is the most common neurodegenerative disease which is induced by the accumulation, oligomerization, and aggregation of amyloid-β peptides (Aβ) due to overproduction and impaired clearance. Cholesterol has reached interest as important risk factor for AD as cholesterol may trigger amyloidogenesis. Since the blood-brain barrier (BBB) is involved in these processes, we investigated the impact of the pharmacologic retinoid-X receptor (RXR) agonist, Bexarotene (Bex), and the peroxisome proliferator-activated receptor-α (PPAR) agonist, carotenoid, and strong antioxidant, astaxanthin (Asx), on regulation of cellular cholesterol metabolism, amyloid precursor protein (APP) processing, Aβ generation and transport at the BBB in vitro using primary porcine brain capillary endothelial cells (pBCEC) and in 3xTg AD model mice. Questions addressed: we here applied the PPARα agonist Asx in order to compare risks and the potential of such treatment to those of Bex. To investigate effects of Bex and Asx in vitro, pBCEC were incubated in the presence or absence of either of both compounds. We investigated amyloidogenic and non-amyloidogenic APP processing pathways, cellular cholesterol metabolism, Aβ clearance and trafficking across the in vitro BBB, and formation of reactive oxygen species. Furthermore, we conducted two mouse studies: in study I, female 3xTg AD and non-Tg mice (C57BL/6; 32-49 weeks) and in study II, aged (68-92 weeks) female 3xTg AD mice were gavaged for 6 days with Bex (100 mg/kg) or Asx (80 mg/kg). Brains and murine (m)BCEC were isolated and transcription and/or protein levels of APP/A species as well as BACE1 and genes involved in cholesterol transport and metabolism were determined. Results: Activity of amyloidogenic BACE1 in response to Bex or Asx was reduced while non-amyloidogenic ADAM10 transcription was up-regulated in pBCEC. Aβ clearance to the apical/plasma compartment of the in vitro BBB model was enhanced after administration of either compound. Applying Bex or Asx increased expression levels of ABCA1, LRP-1, and/or apoA-I. ApoA-I- and HDL3-mediated cholesterol efflux from pBCEC was induced by Bex or Asx in part through RXR/ PPARα activation, while cholesterol biosynthesis and esterification were diminished. Bex or Asx decreased Aβ oligomers and an ~80 kDa intracellular 6E10-reactive APP/A species. Silencing of LRP-1/inhibition of ABCA1 by probucol showed opposite effects of Asx/Bex on levels of ~80 kDa intracellular APP/A in pBCEC. Murine (m)BCEC isolated from 3xTg AD mice treated with Bex showed elevated expression of apoE and ABCA1, while Bex and Asx increased LRP-1 expression and diminished BACE1 expression in mBCEC when compared to vehicle-treated or non-Tg, treated animals. Reduced levels of soluble Aβ oligomers in mBCEC and in brains of 3xTg AD mice were observed upon Bex or Asx administration. In parallel, Asx/Bex diminished Aβ species in brain soluble and insoluble fractions of 3xTg AD mice. Conclusion: Our results strongly suggest that these two different nuclear receptor agonists establish similar protective effects on cholesterol homeostasis and Aβ clearance at the BBB thereby significantly reducing cerebral Aβ burden.