title: Niemann-Pick C1 mice, a model of "juvenile Alzheimer's disease", with normal gene expression in neurons and fibrillary astrocytes show long term survival and delayed neurodegeneration.
abstract: Niemann-Pick C1 (NPC) disease, also known as "juvenile Alzheimer's disease", is a disease in which alterations in intracellular cholesterol trafficking occur. The contribution of various CNS cell types to the neurodegeneration has been of much interest. We have previously shown that expression of the normal gene only in fibrillary astrocytes could extend survival of Npc1-/- mice over 3-fold (Zhang et al., 2008 [13]). We have now studied expression only in neurons or in both neurons and fibrillary astrocytes. Neuron-only expression resulted in survivals of over a year (>5-fold) but motor symptoms started at about 6 months. As reflected in weight gain, this especially affected females who weighed less than wild-type starting at about 10 weeks while male differences in weight are delayed. Expression in both cell types led to a nearly normal phenotype with motor symptoms developing at about ten months and increased survival times. Purkinje cell loss was slowed, but severe, in both NSE- and NSE-GFAP-Npc1, transgenic Npc1-/- mice. MRI studies showed that myelination of the long tracts was significantly improved in NSE-Npc1 transgenics, perhaps less than in GFAP-Npc1 transgenics, and not differently than in the double transgenics. Memory was improved in both single and double transgenics. Somatic disease had not been ameliorated and lungs were massively infiltrated with foamy macrophages at 10 months. Our results suggest that neuron-only expression does not completely prevent neurodegeneration and that the addition of astrocyte expression decreases the rate/degree of decline.
authors.affiliation: Department of Pediatrics, University of Arizona, Tucson, AZ 85724-5073, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Borbon
authors.forename: John
authors.initials: J
authors.lastname: Totenhagen
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Fiorenza
authors.forename: Sonia
authors.initials: S
authors.lastname: Canterini
authors.forename: Wangjing
authors.initials: W
authors.lastname: Ke
authors.forename: Theodore
authors.initials: T
authors.lastname: Trouard
authors.forename: Robert P
authors.initials: RP
authors.lastname: Erickson
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000172:deficiency; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000235:genetics*; D015996:Survival Rate / Q000639:trends; D013997:Time Factors; D033921:Vesicular Transport Proteins
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; C104585:NPC2 protein, human; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D033921:Vesicular Transport Proteins