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Journal of Lipid Research, Vol. 45, 582-591, March 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology
Methods |
* Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03755
Biomembrane Research Group, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan
Department of Pathology, Dartmouth Medical School, Hanover, NH 03755
1 To whom correspondence should be addressed. e-mail: Ta.Yuan.Chang{at}Dartmouth.edu (T-Y.C.); William.F.Hickey{at}Dartmouth.edu (W.F.H.)
Niemann-Pick type C (NPC) is a neurodegenerative disorder characterized by progressive accumulation of cholesterol, gangliosides, and other lipids in the central nervous system and visceral organs. In the NPC1 mouse model, neurodegeneration and neuronal cell loss occur before postnatal day 21. Whether neuronal cholesterol accumulation occurs in vivo before the first signs of neuronal cell loss has not been demonstrated. In this report, we used the NPC1 mouse model and employed a novel cholesterol binding reagent, BC
, that enabled us to visualize cellular cholesterol accumulation at a level previously unattainable.
The results demonstrate the superiority of BC staining over conventional filipin staining in confocal microscopy and highlight several new findings. We show that at postnatal day 9, although only mild signs of neurodegeneration are detectable, significant neuronal cholesterol accumulation has already occurred throughout the NPC1 brain. In addition, although NPC1 Purkinje neurons exhibit a normal morphology at day 9, significant cholesterol accumulation within their extensive dendritic trees has occurred. We also show that in the thalamus and cortex of NPC1 mice, activated glial cells first appear at postnatal day 9 and heavily populate by day 22, suggesting that in NPC1 mice, neuronal cholesterol accumulation precedes neuronal injury and neuronal cell loss.
Abbreviations: CNS, central nervous system; GFAP, glial fibrillary acidic protein; NPC, Niemann-Pick type C; PM, plasma membrane; WT, wild-type
Supplementary key words intracellular cholesterol accumulation • Niemann-Pick Disease • neuron • astrocyte • Purkinje cell • neurodegeneration • BC
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