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

Williams, Ian M.; Wallom, Kerri‐Lee; Smith, David A.; Eisa, Nada Al; Smith, Claire; Platt, Frances M.

doi:10.1016/j.nbd.2014.03.001

Cited by 69 publications

(65 citation statements)

References 47 publications

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“…These findings are in line with our study showing that NPC1 loss results in a strong pro-inflammatory phenotype and dysregulated microglia at early pre-symptomatic disease stage. Accordingly, pharmacological or genetic immune modulations have been shown to be beneficial and improved life expectancy in NPC murine models (Cougnoux et al, 2018, Smith et al, 2009, Williams et al, 2014.…”

Section: Discussionmentioning

confidence: 99%

“…While cell culture experiments suggested that Npc1 -/microglia do not directly trigger neurotoxicity (Peake, Campenot et al, 2011) and microglial ablation in an NPC murine model was not beneficial (Gabande-Rodriguez, Perez-Canamas et al, 2018), additional studies supported beneficial effects of microglial modulation (Cougnoux et al, 2018, Smith et al, 2009, Williams, Wallom et al, 2014. Moreover, significant changes in inflammatory markers were reported in both pre-symptomatic murine model and human NPC cases, suggesting that immune response could be a precocious phenomenon preceding neuronal loss (Baudry et al, 2003, Cluzeau, Watkins-Chow et al, 2012, Cologna et al, 2014, Pressey, Smith et al, 2012.…”

Section: Introductionmentioning

confidence: 99%

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Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia

Colombo

Dinkel

Müller

et al. 2019

Preprint

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Niemann-Pick type C disease is a rare neurodegenerative disorder mainly caused by mutations in Npc1, resulting in abnormal late endosomal/lysosomal lipid storage. Although microgliosis is a prominent pathological feature, consequences of NPC1 loss on microglial function remain uncharacterized. Here, we provide an in-depth characterization of microglial proteomic signatures and phenotypes in a NPC1-deficient (Npc1 -/-) murine model and patient blood-derived macrophages. We demonstrate enhanced phagocytic uptake and impaired lipid trafficking in Npc1 -/microglia that precede neuronal death. Loss of NPC1 compromises microglial developmental functions as revealed by increased synaptic pruning and deficient myelin turnover. Undigested myelin accumulates within multi-vesicular bodies of Npc1 -/microglia while lysosomal degradation remains preserved. To translate our findings to human disease, we generated novel ex vivo assays using patient macrophages that displayed similar proteomic disease signatures and lipid trafficking defects as murine Npc1 -/microglia. Thus, peripheral macrophages provide a novel promising clinical tool for monitoring disease progression and therapeutic efficacy in NPC patients. Our study underscores an essential role for NPC1 in immune cells and implies microglial therapeutic potential.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia

Colombo

Dinkel

Müller

et al. 2019

Preprint

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“…The infantile and late infantile forms are most severe and are characterized by cerebellar ataxia, dementia, cognitive decline, seizures, and premature death (Vanier, 2010). Neuroinflammation comprising microglial activation and proinflammatory cytokine production has been proposed to play an important role in NPC patients and the corresponding mouse model (Baudry, Yao, Simmons, Liu, & Bi, 2003;Cologna et al, 2014;Williams et al, 2014). Accordingly, treatment with antiinflammatory compounds attenuated neurodegeneration and clinical disease in the NPC mouse model (Smith, Wallom, Williams, Jeyakumar, & Platt, 2009;Williams et al, 2014).…”

Section: Niemann-pick Type C (Npc) Is Caused By Inherited Defects In mentioning

confidence: 99%

Neuroinflammation as modifier of genetically caused neurological disorders of the central nervous system: Understanding pathogenesis and chances for treatment

Groh

Martini

2017

Glia

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Genetically caused neurological disorders of the central nervous system (CNS) are usually orphan diseases with poor or even fatal clinical outcome and few or no treatments that will improve longevity or at least quality of life. Neuroinflammation is common to many of these disorders, despite the fact that a plethora of distinct mutations and molecular changes underlie the disorders. In this article, data from corresponding animal models are analyzed to define the roles of innate and adaptive inflammation as modifiers and amplifiers of disease. We describe both common and distinct patterns of neuroinflammation in genetically mediated CNS disorders and discuss the contrasting mechanisms that lead to adverse versus neuroprotective effects. Moreover, we identify the juxtaparanode as a neuroanatomical compartment commonly associated with inflammatory cells and ongoing axonopathic changes, in models of diverse diseases. The identification of key immunological effector pathways that amplify neuropathic features should lead to realistic possibilities for translatable therapeutic interventions using existing immunomodulators. Moreover, evidence emerges that neuroinflammation is not only able to modify primary neural damage-related symptoms but also may lead to unexpected clinical outcomes such as neuropsychiatric syndromes.

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“…It has long been known that peripheral inflammation exacerbates neurodegeneration, suggesting that a simple inflammatory state, whether through primary immune dysfunction or infection, could accelerate disease (93). The use of anti-inflammatories in mouse and cell models of lysosomal storage disorders have supported this notion, although there is no evidence this extends to patients (94–96). Currently, there is no indication that children with NCL are at risk for infection outside that conferred by immobility; however, this has not been systematically studied.…”

Section: Discussionmentioning

confidence: 99%

Antigen presenting cell abnormalities in the Cln3 −/− mouse model of juvenile neuronal ceroid lipofuscinosis

Hersrud

Kovács

Pearce

2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Mutations of the CLN3 gene lead to juvenile neuronal ceroid lipofuscinosis (JNCL), an autosomal recessive lysosomal storage disorder that causes progressive neurodegeneration in children and adolescents. There is evidence of immune system involvement in pathology that has been only minimally investigated. We characterized bone marrow stem cell-derived antigen presenting cells (APCs), peritoneal macrophages, and leukocytes from spleen and blood, harvested from the Cln3−/− mouse model of JNCL. We detected dramatically elevated CD11c surface levels and increased total CD11c protein in Cln3−/− cell samples compared to wild type. This phenotype was specific to APCs and also to a loss of CLN3, as surface levels did not differ from wild type in other leukocyte subtypes nor in cells from two other NCL mouse models. Subcellularly, CD11c was localized to lipid rafts, indicating that perturbation of surface levels is attributable to derangement of raft dynamics, which has previously been shown in Cln3 mutant cells. Interrogation of APC function revealed that Cln3−/− cells have increased adhesiveness to CD11c ligands as well as an abnormal secretory pattern that closely mimics what has been previously reported for Cln3 mutant microglia. Our results show that CLN3 deficiency alters APCs, which can be a major contributor to the autoimmune response in JNCL.

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

Cited by 69 publications

References 47 publications

Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia

Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia

Neuroinflammation as modifier of genetically caused neurological disorders of the central nervous system: Understanding pathogenesis and chances for treatment

Antigen presenting cell abnormalities in the Cln3 −/− mouse model of juvenile neuronal ceroid lipofuscinosis

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