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Current Pharmaceutical Biotechnology
ISSN (Print): 1389-2010
ISSN (Online): 1873-4316
VOLUME: 14
ISSUE: 6
DOI: 10.2174/138920101131400224      Price:  $58









Pharmacological Activation of LXRs Decreases Amyloid-β Levels in Niemann-Pick Type C Model Cells

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Author(s): Jasminka Stefulj, Maja Peric, Martina Malnar, Marko Kosicek, Cornelia Schweinzer, Jelena Zivkovic, Monika Scholler, Ute Panzenboeck and Silva Hecimovic
Pages 582-593 (12)
Abstract:
Niemann-Pick type C disease (NPC) is an inherited disorder mainly caused by loss-of-function mutations in the NPC1 gene, that lead to intracellular cholesterol accumulation and disturbed cholesterol homeostasis. Similarly to Alzheimer's disease (AD), NPC is associated with progressive neurodegeneration and altered metabolism of amyloid precursor protein (APP). Liver X receptors (LXRs), the key transcriptional regulators of cholesterol homeostasis, were reported to play neuroprotective roles in NPC mice. We investigated the impacts of LXRs on APP metabolism in mutant CHO cells lacking the NPC1 gene (-NPC1 cells). Pharmacological activation of LXRs in -NPC1 cells tended to reduce the ratio of total secreted APP (sAPP) to full length APP (flAPP) levels and sAPPβ levels as well as to increase the ratio of APP Cterminal fragments to flAPP levels, resulting in decreased levels of amyloid β (Aβ) peptides. -NPC1 cells treated with LXR agonist TO901317 (TO90) displayed a modest increase in cholesterol efflux to apolipoprotein A-I (apoA-I) but not to HDL3, or in the absence of extracellular cholesterol acceptors. The observed similar reduction of Aβ levels upon TO90 treatment in the presence or in the absence of extracellular apoA-I indicated a cholesterol-efflux independent effect of TO90 on Aβ levels. Furthermore, TO90 had no effect on the cholesterol synthesis rate in -NPC1 cells, while it reduced the rate of cholesterol esterification. The obtained results indicate that LXR activation may decrease Aβ levels in NPC1- deficient conditions. The underlying mechanism of this action does not appear to be related to effects on cholesterol efflux or synthesis rates.
Keywords:
Aβ, ABCA1, Alzheimer's disease, APP, Cholesterol, Liver X receptors, NPC1.
Affiliation:
Laboratory of Neurochemistry and Molecular Neurobiology, Division of Molecular Biology, Rudjer Boskovic Institute, Bijenicka 54, HR-10000 Zagreb, Croatia