Niemann-Pick Disease Type C1 Mouse Research Articles

Accumulation of alkyl-lysophosphatidylcholines in Niemann-Pick disease type C1

Lysosomal function is impaired in Niemann-Pick disease type C1 (NPC1), a rare and inherited neurodegenerative disorder, resulting in late endosomal/lysosomal accumulation of unesterified cholesterol. The precise pathogenic mechanism of NPC1 remains incompletely understood. In this study, we employed metabolomics to uncover secondary accumulated substances in NPC1. Our findings unveiled a substantial elevation in the levels of three alkyl-lysophosphatidylcholine [alkyl-LPC, also known as lyso-platelet activating factor (PAF)] species in NPC1 compared to controls across various tissues, including brain tissue from individuals with NPC1, liver, spleen, cerebrum, cerebellum, and brain stem from NPC1 mice, as well as in both brain and liver tissue from NPC1 cats. The three elevated alkyl-LPC species were as follows: LPC O-16:0, LPC O-18:1, and LPC O-18:0. However, the levels of PAF 16:0, PAF 18:1, and PAF 18:0 were not altered in NPC1. In the NPC1 feline model, the brain and liver alkyl-LPC levels were reduced following 2-hydroxypropyl-β-cyclodextrin (HPβCD) treatment, suggesting that alkyl-LPCs are secondary storage metabolites in NPC1 disease. Unexpectedly, cerebrospinal fluid (CSF) levels of LPC O-16:0 and LPC O-18:1 were decreased in individuals with NPC1 compared to age-appropriate comparison samples, and their levels were increased in 80% of participants 2 years after intrathecal HPβCD treatment. The fold increases in CSF LPC O-16:0 and LPC O-18:1 levels were more pronounced in responders compared to nonresponders. This study identified alkyl-LPC species as secondary storage metabolites in NPC1 and indicates that LPC O-16:0 and LPC O-18:1, in particular, could serve as potential biomarkers for tracking treatment response in NPC1 patients.

Optimization of systemic AAV9 gene therapy in Niemann-Pick disease type C1 mice.

Systemic AAV9- hNPC1 gene therapy in null Npc1 m1N mice at higher doses or with earlier administration and treatment of hypomorphic Npc1 I1061T mice delays disease progression and increases lifespan.

Sterol O-Acyltransferase 1 (SOAT1): A Genetic Modifier of Niemann-Pick Disease, Type C1.

Niemann-Pick disease type C1 (NPC1) is a lysosomal disorder due to impaired intracellular cholesterol transport out of the endolysosomal compartment.. Marked heterogeneity has been observed in individuals with the same NPC1 genotype, thus suggesting a significant effect of modifier genes. Prior work demonstrated that decreased SOAT1 activity decreased disease severity in an NPC1 mouse model. Thus, we hypothesized that a polymorphism associated with decreased SOAT1 expression might influence the NPC1 phenotype. Phenotyping and genomic sequencing of 117 individuals with NPC1 was performed as part of a Natural History trial. Phenotyping included determination of disease severity and disease burden. Significant clinical heterogeneity is present in individuals homozygous for the NPC1I1061T variant and in siblings. Analysis of the SOAT1 polymorphism, rs1044925 (A>C), showed a significant association of the C-allele with earlier age of neurological onset. The C-allele may be associated with a higher Annualized Severity Index Score as well as increased frequency of liver disease and seizures. A polymorphism associated with decreased expression of SOAT1 appears to be a genetic modifier of the NPC1 phenotype. This finding is consistent with prior data showing decreased phenotypic severity in Npc1-/-:Soat1-/- mice and supports efforts to investigate the potential of SOAT1 inhibitors as a potential therapy for NPC1.

Peripheral immune system modulates Purkinje cell degeneration in Niemann-Pick disease type C1.

Niemann-Pick disease type C1 (NPC1) is a fatal lysosomal storage disorder characterized by progressive neuronal degeneration. Its key pathogenic events remain largely unknown. We have, herein, found that neonatal BM-derived cell transplantation can ameliorate Purkinje cell degeneration in NPC1 mice. We subsequently addressed the impact of the peripheral immune system on the neuropathogenesis observed in NPC1 mice. The depletion of mature lymphocytes promoted NPC1 phenotypes, thereby suggesting a neuroprotective effect of lymphocytes. Moreover, the peripheral infusion of CD4-positive cells (specifically, of regulatory T cells) from normal healthy donor ameliorated the cerebellar ataxic phenotype and enhanced the survival of Purkinje cells. Conversely, the depletion of regulatory T cells enhanced the onset of the neurological phenotype. On the other hand, circulating inflammatory monocytes were found to be involved in the progression of Purkinje cell degeneration, whereas the depletion of resident microglia had little effect. Our findings reveal a novel role of the adaptive and the innate immune systems in NPC1 neuropathology.

Improved systemic AAV gene therapy with a neurotrophic capsid in Niemann-Pick disease type C1 mice.

Niemann-Pick C1 disease (NPC1) is a rare, fatal neurodegenerative disease caused by mutations in NPC1, which encodes the lysosomal cholesterol transport protein NPC1. Disease pathology involves lysosomal accumulation of cholesterol and lipids, leading to neurological and visceral complications. Targeting the central nervous system (CNS) from systemic circulation complicates treatment of neurological diseases with gene transfer techniques. Selected and engineered capsids, for example, adeno-associated virus (AAV)-PHP.B facilitate peripheral-to-CNS transfer and hence greater CNS transduction than parental predecessors. We report that systemic delivery to Npc1 m1N/m1N mice using an AAV-PHP.B vector ubiquitously expressing NPC1 led to greater disease amelioration than an otherwise identical AAV9 vector. In addition, viral copy number and biodistribution of GFP-expressing reporters showed that AAV-PHP.B achieved more efficient, albeit variable, CNS transduction than AAV9 in Npc1 m1N/m1N mice. This variability was associated with segregation of two alleles of the putative AAV-PHP.B receptor Ly6a in Npc1 m1N/m1N mice. Our data suggest that robust improvements in NPC1 disease phenotypes occur even with modest CNS transduction and that improved neurotrophic capsids have the potential for superior NPC1 AAV gene therapy vectors.

Sex-opposed inflammatory effects of 27-hydroxycholesterol are mediated via differences in estrogen signaling.

Despite the increased awareness of differences in the inflammatory response between men and women, only limited research has focused on the biological factors underlying these sex differences. The cholesterol derivative 27‐hydroxycholesterol (27HC) has been shown to have opposite inflammatory effects in independent experiments using mouse models of atherosclerosis and non‐alcoholic steatohepatitis (NASH), pathologies characterized by cholesterol‐induced inflammation. As the sex of mice in these in vivo models differed, we hypothesized that 27HC exerts opposite inflammatory effects in males compared to females. To explore whether the sex‐opposed inflammatory effects of 27HC translated to humans, plasma 27HC levels were measured and correlated with hepatic inflammatory parameters in obese individuals. To investigate whether 27HC exerts sex‐opposed effects on inflammation, we injected 27HC into female and male Niemann–Pick disease type C1 mice (Npc1 nih) that were used as an extreme model of cholesterol‐induced inflammation. Finally, the involvement of estrogen signaling in this mechanism was studied in bone marrow‐derived macrophages (BMDMs) that were treated with 27HC and 17β‐estradiol (E2). Plasma 27HC levels showed opposite correlations with hepatic inflammatory indicators between female and male obese individuals. Likewise, hepatic 27HC levels oppositely correlated between female and male Npc1 nih mice. Twenty‐seven hydroxycholesterol injections reduced hepatic inflammation in female Npc1 nih mice in contrast to male Npc1 nih mice, which showed increased hepatic inflammation after 27HC injections. Furthermore, 27HC administration also oppositely affected inflammation in female and male BMDMs cultured in E2‐enriched medium. Remarkably, female BMDMs showed higher ERα expression compared to male BMDMs. Our findings identify that the sex‐opposed inflammatory effects of 27HC are E2‐dependent and are potentially related to differences in ERα expression between females and males. Hence, the individual’s sex needs to be taken into account when 27HC is employed as a therapeutic tool as well as in macrophage estrogen research in general. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Iron chelation by deferiprone does not rescue the Niemann-Pick Disease Type C1 mouse model.

Niemann-Pick Disease Type C (NP-C) is a fatal lysosomal storage disorder with progressive neurodegeneration. In addition to the characteristic cholesterol and lipid overload phenotype, we previously found that altered metal homeostasis is also a pathological feature. Increased brain iron in the Npc1-/- mouse model of NP-C may potentially contribute to neurodegeneration, similar to neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Deferiprone (DFP) is a brain penetrating iron chelator that has demonstrated effectiveness in preventing neurological deterioration in Parkinson's disease clinical trials. Therefore, we hypothesized that DFP treatment, targeting brain iron overload, may have therapeutic benefits for NP-C. Npc1-/- mice were assigned to four experimental groups: (1) pre-symptomatic (P15) + 75 mg/kg DFP; (2) pre-symptomatic (P15) + 150 mg/kg DFP; (3) symptomatic (P49) + 75 mg/kg DFP; (4) symptomatic (P49) + 150 mg/kg DFP. Our study found that in Npc1-/- mice, DFP treatment did not offer any improvement over the expected disease trajectory and median lifespan. Moreover, earlier treatment and higher dose of DFP resulted in adverse effects on body weight and onset of ataxia. The outcome of our study indicated that, despite increased brain iron, Npc1-/- mice were vulnerable to pharmacological iron depletion, especially in early life. Therefore, based on the current model, iron chelation therapy is not a suitable treatment option for NP-C.

Maternal immune activation modifies the course of Niemann-pick disease, type C1 in a gender specific manner

Niemann-Pick disease, type C1 (NPC1) is a rare neurodegenerative lysosomal storage disease with a wide spectrum of clinical manifestation. Multiple genetic factors influence the NPC1 mouse phenotype, but very little attention has been given to prenatal environmental factors that might have long-term effects on the neuroinflammatory component of NPC1 pathology. Studies in other mouse models of cerebellar ataxia have shown that developmental exposures lead to Purkinje neuron degeneration later in life, suggesting that environmental exposures during development can impact cerebellar biology. Thus, we evaluated the potential effect of maternal immune activation (MIA) on disease progression in an Npc1 mouse model. The MIA paradigm used mimics viral infection using the toll like receptor 3 agonist polyinosinic-polycytidilic acid during gestation. Through phenotypic and pathologic tests, we measured motor and behavioral changes as well as cerebellar neuroinflammation and neurodegeneration. We observed a gender and genotype dependent effect of MIA on the cerebellum. While the effects of MIA have been previously shown to primarily affect male progeny, we observed increased sensitivity of female mutant progeny to prenatal exposure to treatment with polyinosinic-polycytidilic acid. Specifically, prenatal MIA resulted in female NPC1 mutant progeny with greater motor deficits and a corresponding decrease in cerebellar Purkinje neurons. Our data suggest that prenatal environmental exposures may be one factor contributing to the phenotypic variability observed in individuals with NPC1.

Main Olfactory and Vomeronasal Epithelium Are Differently Affected in Niemann-Pick Disease Type C1.

Introduction: Olfactory impairment is one of the earliest symptoms in neurodegenerative disorders that has also been documented in Niemann-Pick disease type C1 (NPC1). NPC1 is a very rare, neurovisceral lipid storage disorder, characterized by a deficiency of Npc1 gene function that leads to progressive neurodegeneration. Here, we compared the pathologic effect of defective Npc1 gene on the vomeronasal neuroepithelium (VNE) with that of the olfactory epithelium (OE) in an NPC1 mouse model. Methods: Proliferation in the VNE and OE was assessed by applying a bromodeoxyuridine (BrdU) protocol. We further compared the immunoreactivities of anti-olfactory marker protein (OMP), and the lysosomal marker cathepsin-D in both epithelia. To investigate if degenerative effects of both olfactory systems can be prevented or reversed, some animals were treated with a combination of miglustat/allopregnanolone/2-hydroxypropyl-cyclodextrin (HPβCD), or a monotherapy with HPβCD alone. Results: Using BrdU to label dividing cells of the VNE, we detected a proliferation increase of 215% ± 12% in Npc1−/− mice, and 270% ± 10% in combination- treated Npc1−/− animals. The monotherapy with HPβCD led to an increase of 261% ± 10.5% compared to sham-treated Npc1−/− mice. Similar to the OE, we assessed the high regenerative potential of vomeronasal progenitor cells. OMP reactivity in the VNE of Npc1−/− mice was not affected, in contrast to that observed in the OE. Concomitantly, cathepsin-D reactivity in the VNE was virtually absent. Conclusion: Vomeronasal receptor neurons are less susceptible against NPC1 pathology than olfactory receptor neurons. Compared to control mice, however, the VNE of Npc1−/− mice displays an increased neuroregenerative potential, indicating compensatory cell renewal.

Necroptosis inhibition as a therapy for Niemann-Pick disease, type C1: Inhibition of RIP kinases and combination therapy with 2-hydroxypropyl-β-cyclodextrin

Niemann-Pick disease, type C1 (NPC1) is an inborn error of metabolism that results in endolysosomal accumulation of unesterified cholesterol. Clinically, NPC1 manifests as cholestatic liver disease in the newborn or as a progressive neurogenerative condition characterized by cerebellar ataxia and cognitive decline. Currently there are no FDA approved therapies for NPC1. Thus, understanding the pathological processes that contribute to neurodegeneration will be important in both developing and testing potential therapeutic interventions. Neuroinflammation and necroptosis contribute to the NPC1 pathological cascade. Receptor Interacting Protein Kinase 1 and 3 (RIPK1 and RIPK3), are protein kinases that play a central role in mediating neuronal necroptosis. Our prior work suggested that pharmacological inhibition of RIPK1 had a significant but modest beneficial effect; however, the inhibitors used in that study had suboptimal pharmacokinetic properties. In this work we evaluated both pharmacological and genetic inhibition of RIPK1 kinase activity. Lifespan in both Npc1−/− mice treated with GSK′547, a RIPK1 inhibitor with better pharmacokinetic properties, and Npc1−/−:Ripk1kd/kd double mutant mice was significantly increased. In both cases the increase in lifespan was modest, suggesting that the therapeutic potential of RIPK1 inhibition, as a monotherapy, is limited. We thus investigated the potential of combining RIPK1 inhibition with 2-hydroxypropyl-β-cyclodextrin (HPβCD) therapy HPβCD has been shown to slow neurological disease progression in NPC1 mice, cats and patients. HPβCD appeared to have an additive positive effect on the pathology and survival of Npc1−/−:Ripk1kd/kd mice. RIPK1 and RIPK3 are both critical components of the necrosome, thus we were surprised to observe no increase survival in Npc1−/−;Ripk3−/− mice compared to Npc1−/− mice. These data suggest that although necroptosis is occurring in NPC1, the observed effects of RIPK1 inhibition may be related to its RIPK3-independent role in neuroinflammation and cytokine production.

In Niemann-Pick C1 mouse models, glial-only expression of the normal gene extends survival much further than do changes in genetic background or treatment with hydroxypropyl-beta-cyclodextrin

The Npc1nmf164 allele of Npc1 provides a mouse model for Niemann-Pick disease type C1 (NPC1), a genetic disease known to have a widely variable phenotype. The transfer of the Npc1nmf164 mutation from the C57BL/6J inbred strain to the BALB/cJ inbred strain increased the mean lifespan from 117.8days to 153.1days, confirming that the severity of the NPC1 phenotype is strongly influenced by genetic background. The transfer of another Npc1 allele, Npc1nih, to this background also extended survival of the homozygotes indicating that the modifying effect of BALB/cJ is not limited to a single allele of Npc1. The increased longevity due to the BALB/cJ background did not map to a previously mapped modifier on chromosome 19, indicating the presence of additional genes impacting disease severity. The previously studied Glial Fibrillary Acidic Protein promoter-Npc1 cDNA transgene (GFAP-Npc1) which only expresses NPC1 in astrocytes further extended the lifespan of Npc1nmf164 homozygotes on a BALB/cJ background (up to 600days). Hydroxypropyl-β-cyclodextrin (HPβCD) treatment, not previously tested in the Npc1nmf164 mutant, extended life in the Npc1nmf164 homozygotes but not the transgenic, Npc1nmf164 mice on the BALB/cJ background. In all cases, lack of weight gain and early cerebellar symptoms of loss of motor control were found. At termination, the one mouse sacrificed for histological studies showed severe, diffuse pulmonary alveolar proteinosis suggesting that pulmonary abnormalities in NPC1 mouse models are not unique to the Npc1nih allele.

Protective mechanism in NPC1 – the role of oxLDL

The Niemann Pick disease type C1 (NPC1) is a lysosomal storage disorder caused by a mutation in the NPC1 gene. The mutation disrupts the normal cholesterol traficking and induces cholesterol accumulation in cells of the liver and the brain. Till now, no therapy exists for NPC1 patients. But recently, pneumococci immunization has shown to reduce inflammation in Non-alcoholic steatohepatitis (NASH), another lipid storage disorder. Therefore, pneumococci immunization was also tested on NPC1mut mice. The results indicate an improved pathology in the NPC1 mice after the immunization

Defective macrophage phagocytosis and particle clearance in Niemann-Pick disease type C1 mice

Defective macrophage phagocytosis and particle clearance in Niemann-Pick disease type C1 mice

Fusion of Lysosomes with Secretory Vesicle Leads to Excessive Uncontrolled Exocytosis in Mucolipidosis Type IV

Mutations in TRPML1 cause the lysosomal storage disease (LSD) Mucolipidosis type IV (MLIV), which is characterized by neurodegeneration, muscular hypotonia corneal opacity, achlorhydia, anemia and severe psychomotor deficiency with impaired neuromuscular junctions. The role of the TRP channel TRPML1 in cell function and how mutations in TRPML1 cause MLIV are not well understood. Studies on the causes of MLIV are focused on the potential role of TRPML1 in constitutive membrane trafficking to and from the lysosomes. However, the role of TRPML1 in secretory cells that their cardinal function is regulated exocytosis has not been studied. Here, we analyzed several forms of regulated exocytosis in neurons and secretory epithelia in a knockout mouse model of TRPML1 and, unexpectedly, found excessive exocytosis due to marked enlargement of synaptic vesicles and secretory granules due to fusion with lysosomes. As a result, Trpml1−/− neurons maintain high basal and stimulated exocytosis of the neurotransmitter and neurotoxin glutamate, which may account for the neurodegeneration in ML4. Trpml1−/− pancreatic and salivary glands acini show high Ca2+− and cAMP-stimulated exocytosis, resulting in pancreatitis. These features were not found in another model of LSD, the Niemann-Pick disease type C1 mouse model. These findings indicate that a major role of TRPML1 is to guard against pathological fusion of lysosomes with other intracellular organelles, including secretory vesicles, and suggest a new approach towards developing treatment for MLIV.

Excessive microglial activation aggravates olfactory dysfunction by impeding the survival of newborn neurons in the olfactory bulb of Niemann–Pick disease type C1 mice

Progressive olfactory impairment is one of the earliest markers of neurodegeneration. However, the underlying mechanism for this dysfunction remains unclear. The present study investigated the possible role of microgliosis in olfactory deficits using a mouse model of Niemann–Pick disease type C1 (NPC1), which is an incurable neurodegenerative disorder with disrupted lipid trafficking. At 7weeks of age, NPC1 mutants showed a distinct olfactory impairment in an olfactory test compared with age-matched wild-type controls (WT). The marked loss of olfactory sensory neurons within the NPC1 affected olfactory bulb (NPC1-OB) suggests that NPC1 dysfunction impairs olfactory structure. Furthermore, the pool of neuroblasts in the OB was diminished in NPC1 mice despite the intact proliferative capacity of neural stem/progenitor cells in the subventricular zone. Instead, pro-inflammatory proliferating microglia accumulated extensively in the NPC1-OB as the disease progressed. To evaluate the impact of abnormal microglial activation on olfaction in NPC1 mice, a microglial inhibition study was performed using the anti-inflammatory agent Cyclosporin A (CsA). Importantly, long-term CsA treatment in NPC1 mice reduced reactive microgliosis, restored the survival of newly generated neurons in the OB and improved overall performance on the olfactory test. Therefore, our study highlights the possible role of microglia in the regulation of neuronal turnover in the OB and provides insight into the possible therapeutic applications of microglial inhibition in the attenuation or reversal of olfactory impairment.

Improved neuroprotection using miglustat, curcumin and ibuprofen as a triple combination therapy in Niemann–Pick disease type C1 mice

ObjectivesNiemann–Pick disease type C (NPC) is a neurodegenerative lysosomal storage disorder characterised by the storage of multiple lipids, reduced lysosomal calcium levels, impaired late endosome:lysosome fusion and neuroinflammation. NPC is caused by mutations in either of the two genes, NPC1 or NPC2, which are believed to function in a common cellular pathway, the function of which remains unclear. The complexity of the pathogenic cascade in NPC disease provides a number of potential clinical intervention points. To date, drugs that target pivotal stages in the pathogenic cascade have been tested as monotherapies or in combination with a second agent, showing additive or synergistic benefit. In this study, we have investigated whether we can achieve greater therapeutic benefit in the Npc1−/− mouse by combining three therapies that each targets unique aspects of the pathogenic cascade. MethodsWe have treated Npc1−/− mice with miglustat that targets sphingolipid synthesis and storage, curcumin that compensates for the lysosomal calcium defect by elevating cytosolic calcium, and the non-steroidal anti-inflammatory drug ibuprofen to reduce central nervous system inflammation. Results/interpretationWe have found that triple combination therapy has a greater neuroprotective benefit compared with single and dual therapies, increasing the time period that Npc1−/− mice maintained body weight and motor function and maximally delaying the onset of Purkinje cell loss. In addition, ibuprofen selectively reduced microglial activation, while curcumin had no anti-inflammatory effects, indicating differential mechanisms of action for these two therapies. When taken together, these results demonstrate that targeting multiple unique steps in the pathogenic cascade maximises the clinical benefit in a mouse model of NPC1 disease.

Therapeutic effects of human amniotic epithelial stem cells in Niemann–Pick type C1 mice

Niemann-Pick disease type C1 (NPC) is an autosomal recessive cholesterol-storage disorder characterized by liver dysfunction, hepatosplenomegaly and progressive neurodegeneration. Thus far, studies of NPC mice have been performed mainly to study the brain and neurodegeneration, because degeneration in the brain was known as the primary cause of death in NPC mice. However, NPC is a systemic disease; therefore the purpose of this study was to find the possibility of a general therapeutic effect by applying and tracking transplanted human amniotic epithelial stem cells (hAESC) in NPC mice. hAESC were administered to NPC homozygous (NPC(-/-)) mice via intravenous injection from 5 weeks of age; each recipient received 5 × 10(5) cells every other week. The body weight of each of the mice was measured every week, and the survival and state of each mouse was evaluated every day. The weight of the organs was measured, and serum chemistry, histology and the intensity of Filipin staining were evaluated. The effect of cell transplantation was to extend the life span and reduce the rapid loss of weight. Moreover, alleviation of tissue damage was observed more in hAESC-treated NPC(-/-) mice than in non-treated NPC(-/-) mice. Cholesterol deposition was reduced after transplantation, and the relative weight of the liver was also decreased. These data show that hAESC could delay the degeneration caused by fatal genetic disorders such as NPC. This study presents the prospect of relief of precipitous disease progression and the therapeutic possibility of applying hAESC to fatal genetic disorders.

Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Protect against Neuronal Cell Death and Ameliorate Motor Deficits in Niemann Pick Type C1 Mice

Niemann Pick disease type C1 (NPC) is an autosomal recessive disease characterized by progressive neurological deterioration leading to premature death. In this study, we hypothesized that human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) have the multifunctional abilities to ameliorate NPC symptoms in the brain. To test this hypothesis, hUCB-MSCs were transplanted into the hippocampus of NPC mice in the early asymptomatic stage. This transplantation resulted in the recovery of motor function in the Rota Rod test and impaired cholesterol homeostasis leading to increased levels of cholesterol efflux-related genes such as LXRα, ABCA1, and ABCG5 while decreased levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase were observed in NPC mice. In the cerebrum, hUCB-MSCs enhanced neuronal cell survival and proliferation, where they directly differentiated into electrically active MAP2-positive neurons as demonstrated by whole-cell patch clamping. In addition, we observed that hUCB-MSCs reduced Purkinje neuronal loss by suppression of inflammatory and apoptotic signaling in the cerebellum as shown by immunohistochemistry. We further investigated how hUCB-MSCs enhance cellular survival and inhibit apoptosis in NPC mice. Neuronal cell survival was associated with increased PI3K/AKT and JAK2/STAT3 signaling; moreover, hUCB-MSCs modulated the levels of GABA/glutamate transporters such as GAT1, EAAT2, EAAT3, and GAD6 in NPC mice as assessed by Western blot analysis. Taken together, our findings suggest that hUCB-MSCs might play multifunctional roles in neuronal cell survival and ameliorating motor deficits of NPC mice.

Beneficial effects of anti-inflammatory therapy in a mouse model of Niemann-Pick disease type C1

Niemann-Pick disease type C1 (NPC1) is a neurodegenerative lysosomal disorder characterized by sphingolipid and cholesterol storage in the late endocytic system. In common with other neurodegenerative diseases, activation of the innate immune system occurs in the brain resulting in neuro-inflammation. Targeting inflammation in the brain therefore represents a potential clinical intervention strategy that aims to slow the rate of disease progression and improve quality of life. We evaluated non-steroidal anti-inflammatory drugs (NSAIDs) and an anti-oxidant to determine whether these agents are disease modifying in an acute mouse model of NPC1. NSAIDs significantly prolonged the lifespan of NPC1 mice and slowed the onset of clinical signs. However, anti-oxidant therapy was of no significant benefit. Combining NSAID therapy with substrate reduction therapy (SRT) resulted in additive benefit. These data suggest that anti-inflammatory therapy may be a useful adjunctive treatment in the clinical management of NPC1, alone or combined with SRT.