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Papers In Press, published online ahead of print January 1, 2004
J. Lipid Res., doi:10.1194/jlr.D300032-JLR200
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Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03755
Corresponding Author: Ta.Yuan.Chang{at}Dartmouth.edu
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. Recently, in the NPC1 mouse model, neuronal cholesterol accumulation in vivo was reported to occur as early as postnatal day 21, before the clinical symptoms of NPC disease manifest (4-6 wks of age). However, neurodegeneration and neuronal cell loss in NPC disease has been reported to occur before postnatal day 21, with the earliest signs of neurodegeneration reported at postnatal day 9. 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-theta that enables us to visualize cellular cholesterol accumulation at a level previously unattainable. The results demonstrate the superiority of BC-theta staining over conventional filipin staining in confocal microscopy, and highlight a number of new findings. We show that at postnatal day 9, while only mild signs of neurodegeneration are detectable, significant neuronal cholesterol accumulation already occurs throughout the NPC1 brain. In addition, while NPC1 Purkinje neurons exhibit a normal morphology at day 9, significant cholesterol accumulation within their extensive dendritic trees occurs. 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 in addition to neuronal cell loss.
Revised on December 17, 2003
Accepted on December 17, 2003
A novel cholesterol stain reveals early neuronal cholesterol accumulation in the Niemann-Pick type C1 mouse brain
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