Human and mouse neuroinflammation markers in Niemann‐Pick disease, type C1

Abstract

Niemann-Pick Disease, type C1 (NPC1) is an autosomal recessive lipid storage disorder in which a pathological cascade, including neuroinflammation occurs. While data demonstrating neuroinflammation is prevalent in mouse models, data from NPC1 patients is lacking. The current study focuses on identifying potential markers of neuroinflammation in NPC1 from both the Npc1 mouse model and NPC1 patients. We identified in the mouse model significant changes in expression of genes associated with inflammation and compared these results to the pattern of expression in human cortex and cerebellar tissue. From gene expression array analysis, complement 3 (C3) was increased in mouse and human post-mortem NPC1 brain tissues. We also characterized protein levels of inflammatory markers in cerebrospinal fluid (CSF) from NPC1 patients and controls. We found increased levels of interleukin 3, chemokine (C-X-C motif) ligand 5, interleukin 16 and chemokine ligand 3 (CCL3), and decreased levels of interleukin 4, 10, 13 and 12p40 in CSF from NPC1 patients. CSF markers were evaluated with respect to phenotypic severity. Miglustat treatment in NPC1 patients slightly decreased IL-3, IL-10 and IL-13 CSF levels; however, further studies are needed to establish a strong effect of miglustat on inflammation markers. The identification of inflammatory markers with altered levels in the cerebrospinal fluid of NPC1 patients may provide a means to follow secondary events in NPC1 disease during therapeutic trials.

Altered transition metal homeostasis in Niemann–Pick disease, type C1

“…However, in contrast to decreased CSF holo-CP in AD, our analysis of the NP-C1 CSF revealed a modest but significant positive association between CSF total and holo-CP concentrations and disease severity (Figure 5A). CP is an acute phase marker and this association may reflect the increase in neuroinflammation in NP-C1 51 . Thus CSF CP may be a useful biomarker to monitor the disease progression and therapeutic response, in addition to the other CSF neuroinflammatory markers identified in the Cologna et al study 51 .…”

“…CP is an acute phase marker and this association may reflect the increase in neuroinflammation in NP-C1 51 . Thus CSF CP may be a useful biomarker to monitor the disease progression and therapeutic response, in addition to the other CSF neuroinflammatory markers identified in the Cologna et al study 51 .…”

Plasma Signature of Neurological Disease in the Monogenetic Disorder Niemann-Pick Type C

“…Inflammatory proteins corresponding to members of chemokines and cytokines family have been explored in cerebrospinal fluid of NPC patients; however, further investigation is required to establish their usefulness as biomarkers (54). Oxysterols largely reflect liver function, although 24(S)-HC has been proposed as a marker for neuronal disease in humans because it is produced in the brain.…”

11‐Month‐Old Infant With Periodic Fevers, Recurrent Liver Dysfunction, and Perforin Gene Polymorphism

“…One further consideration is Niemann-Pick Disease Type C, which is a lysosomal storage disease leading to progressive organomegaly and neurologic dysfunction (3). Recent work has suggested that liver and neurologic dysfunction in Niemann-Pick is an inflammatory process, although signs of severe systemic inflammation as seen in this patient are uncommon (4). Additionally, liver biopsy did not show evidence for a storage disease.…”