title: A novel cholesterol stain reveals early neuronal cholesterol accumulation in the Niemann-Pick type C1 mouse brain.
abstract: 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 theta, that enabled 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 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.
authors.affiliation: Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03755, USA.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Reid
authors.forename: Naomi
authors.initials: N
authors.lastname: Sakashita
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sugii
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Ohno-Iwashita
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Shimada
authors.forename: William F
authors.initials: WF
authors.lastname: Hickey
authors.forename: Ta-Yuan
authors.initials: TY
authors.lastname: Chang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001923:Brain Chemistry; D002784:Cholesterol / Q000032:analysis* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008818:Mice, Neurologic Mutants; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011506:Proteins / Q000235:genetics; D013194:Staining and Labeling / Q000379:methods*; D013997:Time Factors
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D002784:Cholesterol