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.

Developmental delay in motor skill acquisition in Niemann-Pick C1 mice reveals abnormal cerebellar morphogenesis

“…This finding is in agreement with previous observations showing the expression of low-/very low-density lipoprotein receptors by oligodendrocytes [40] and the dependence on glia-derived cholesterol of Npc1-deficient brains [41, 42]. Moreover, dysmyelination and myelin loss were previously reported in prefrontal cortex, corpus callosum and hippocampus of Npc1 −/− mice [43] and found to be associated with defective genetic control of oligodendrocyte differentiation [44].…”

Quantitative magnetic resonance imaging of brain atrophy in a mouse model of Niemann-Pick type C disease

“…The neocortical volume loss we found correlates with the findings of a quantitative ex vivo study of regional brain volumes in 11 week old Npc1 -/- mice which used a stereological cell counting method and found significantly decreased numbers of neurons in the prefrontal cortex (as well as the thalamus)[47]. Memory loss [48] is a consequence of this neocortical and, also, the hippocampal volume losses.…”

Lipid rafts, synaptic transmission and plasticity: Impact in age-related neurodegenerative diseases

“…The relevance of simultaneous interventions over cholesterol trafficking in both astrocytes and neurons to increase survival and decrease the rate of cognitive decline in an animal model of Pick's disease has been put forward recently (Borbon et al, 2012). That brain cholesterol regulation may prove a useful therapeutic strategy for Hungtinton's disease was also recently advanced (Karasinska and Hayden, 2011).…”