Send to:

Choose Destination
See comment in PubMed Commons below
J Biol Chem. 2012 Mar 16;287(12):9290-8. doi: 10.1074/jbc.M111.326405. Epub 2012 Jan 25.

Normalization of cholesterol homeostasis by 2-hydroxypropyl-β-cyclodextrin in neurons and glia from Niemann-Pick C1 (NPC1)-deficient mice.

Author information

  • 1Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.


Niemann-Pick C (NPC) disease is an inherited, progressive neurodegenerative disorder caused by mutations in the NPC1 or NPC2 gene that result in an accumulation of unesterified cholesterol in late endosomes/lysosomes (LE/L) and impaired export of cholesterol from LE/L to the endoplasmic reticulum (ER). Recent studies demonstrate that administration of cyclodextrin (CD) to Npc1(-/-) mice eliminates cholesterol sequestration in LE/L of many tissues, including the brain, delays neurodegeneration, and increases lifespan of the mice. We have now investigated cholesterol homeostasis in NPC1-deficient cells of the brain in response to CD. Primary cultures of neurons and glial cells from Npc1(-/-) mice were incubated for 24 h with 0.1 to 10 mm CD after which survival and cholesterol homeostasis were monitored. Although 10 mm CD was profoundly neurotoxic, and altered astrocyte morphology, 0.1 and 1 mm CD were not toxic but effectively mobilized stored cholesterol from the LE/L as indicated by filipin staining. However, 0.1 and 1 mm CD altered cholesterol homeostasis in opposite directions. The data suggest that 0.1 mm CD releases cholesterol trapped in LE/L of neurons and astrocytes and increases cholesterol availability at the ER, whereas 1 mm CD primarily extracts cholesterol from the plasma membrane and reduces ER cholesterol. These studies in Npc1(-/-) neurons and astrocytes establish a dose of CD (0.1 mm) that would likely be beneficial in NPC disease. The findings are timely because treatment of NPC disease patients with CD is currently being initiated.

[PubMed - indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk