Hepatic and neuronal phenotype of NPC1−/− mice. Issue 3 (March 2019)

• Record Type: Journal Article
• Authors: Santiago-Mujica, Estibaliz; Flunkert, Stefanie; Rabl, Roland; Neddens, Joerg; Loeffler, Tina; Hutter-Paier, Birgit
• Is Part Of: Heliyon. Volume 5:Issue 3(2019)
• Publication Date: 2019-03
• Subjects: Cell biology -- Molecular biology -- Neuroscience -- Physiology; AAALAC Association for Assessment and Accreditation of Laboratory Animal Care -- ALT alanine aminotransferase -- ANOVA Analysis of variance -- AOI Area of interest -- AP alkaline phosphatase -- APP Amyloid Precursor Protein -- AST aspartate aminotransferase -- CD45 cluster of differentiation 45 -- CNS central nervous system -- DAPI 4′, 6-Diamidin-2-phenylindol -- GFAP Glial fibrillary acidic protein -- IFN-γ Interferon-gamma -- IL-10/12 Interleukin-10/12 -- KC keratinocyte chemoattractant -- MAP2 microtubuli-associated protein 2 -- NPC Niemann-Pick type C -- TNF-α tumor necrosis factor-alpha -- WT wildtype; Research -- Periodicals; Medical sciences -- Periodicals; Natural history -- Periodicals; Social sciences -- Periodicals; Earth sciences -- Periodicals; Physical sciences -- Periodicals; 507.2
• DOI: 10.1016/j.heliyon.2019.e01293
• Languages: English
• ISSNs: 2405-8440

Abstract

Abstract: Niemann-Pick type C disease (NPC) is a fatal autosomal recessive disorder characterized by a defect in the intracellular transport of lipoproteins leading to the accumulation of lipids in diverse tissues. A visceral and neuronal phenotype mimicking human NPC1 disease has been described in NPC1 mutant mice. These mice are by now the most widely used NPC1 rodent model to study NPC and developmental compounds against this devastating disease. Here we characterized NPC1 −/− mice for their hepatic and neuronal phenotype to confirm the stability of the phenotype, provide a characterization of disease progression and pinpoint the age of robust phenotype onset. Animals of 4–10 weeks of age were analyzed for general health, motor deficits as well as hepatic and neuronal alterations with a special focus on cerebellar pathology. Our results show that NPC1 −/− mice have a reduced general health at the age of 9–10 weeks. Robust motor deficits can be observed even earlier at 8 weeks of age. Hepatic changes included increased organ weight and cholesterol levels at 6 weeks of age accompanied by severely increased liver enzyme levels. Analysis of NPC1 −/− brain pathology showed decreased cholesterol and increased Aβ levels in the hippocampus at the age of 6 weeks. Further analysis revealed a decrease of the cytokine IL-12p70 in the cerebellum along with a very early increase of astrocytosis. Hippocampal IL-12p70 levels were increased at the age of 6 weeks followed by increased activated microglia levels. By the age of 10 weeks, also cerebellar Aβ levels were increased along with strongly reduced Calbindin D-28k levels. Our results validate and summarize the progressive development of the hepatic and neuronal phenotype of NPC1 −/− mice that starts with cerebellar astrocytosis, making this mouse model a valuable tool for the development of new compounds against NPC.