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.
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