Abstract
Niemann-Pick type C (NPC) disease, a rare autosomal recessive disorder caused mostly by mutation in NPC1 gene, is pathologically characterized by the accumulation of free cholesterol in brain and other tissues. This is accompanied by gliosis and loss of neurons in selected brain regions, including the cerebellum. Recent studies have shown that NPC disease exhibits intriguing parallels with Alzheimer’s disease, including the presence of neurofibrillary tangles and increased levels of amyloid precursor protein (APP)-derived β-amyloid (Aβ) peptides in vulnerable brain neurons. To evaluate the role of Aβ in NPC disease, we determined the gene expression profile in selected brain regions of our recently developed bigenic ANPC mice, generated by crossing APP transgenic (Tg) mice with heterozygous Npc1-deficient mice. The ANPC mice exhibited exacerbated neuronal and glial pathology compared to other genotypes [i.e., APP-Tg, double heterozygous (Dhet), Npc1-null and wild-type mice]. Analysis of expression profiles of 86 selected genes using real-time RT-PCR arrays showed a wide-spectrum of alterations in the four genotypes compared to wild-type controls. The changes observed in APP-Tg and Dhet mice are limited to only few genes involved mostly in the regulation of cholesterol metabolism, whereas Npc1-null and ANPC mice showed alterations in the expression profiles of a number of genes regulating cholesterol homeostasis, APP metabolism, vesicular trafficking and cell death mechanism in both hippocampus and cerebellum compared to wild-type mice. Intriguingly, ANPC and Npc1-null mice, with some exceptions, exhibited similar changes, although more genes were differentially expressed in the affected cerebellum than the relatively spared hippocampus. The altered gene profiles were found to match with the corresponding protein levels. These results suggest that lack of Npc1 protein can alter the expression profile of selected transcripts as well as proteins, and APP overexpression influences cerebral pathology by enhancing changes triggered by Npc1 deficiency in the bigenic line.
Highlights
Niemann-Pick type C (NPC) disease is an autosomal recessive neurovisceral disorder caused predominantly by mutations in the NPC1 gene and less frequently in the NPC2 gene
To evaluate the potential role of Ab peptides in pathological abnormalities related to NPC disease, we have recently developed a new line of bigenic ANPC mice by crossing heterozygous Npc1-deficient mice with mutant human amyloid precursor protein (APP) transgenic (APP-Tg) mice which exhibit extracellular Ab deposits and spatial learning deficits but no overt loss of neurons in any brain region
We focused on the expression of 86 selected genes that are involved in APP and Ab metabolism, cholesterol homeostasis, intracellular vesicular trafficking and cell death mechanisms in the affected cerebellar and relatively spared hippocampal regions of ANPC, Npc1-null, APP-Tg and double heterozygous (Dhet) mice compared to wild-type (WT) controls
Summary
Niemann-Pick type C (NPC) disease is an autosomal recessive neurovisceral disorder caused predominantly by mutations in the NPC1 gene and less frequently in the NPC2 gene. The loss of function of either protein leads to intracellular accumulation of unesterified cholesterol and glycosphingolipids in many tissues, including the brain. These defects in cholesterol sequestration trigger widespread neurological deficits such as ataxia, dystonia, seizures and dementia leading to premature death [1,2,3]. Overall increase in the level or intracellular accumulation of cholesterol is known to trigger generation of Ab peptides by proteolytic processing of amyloid precursor protein (APP), the functional significance of these peptides in NPC pathology remains unclear [13,14,15,16]
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