Abstract
Niemann-Pick type C (NPC) disease, sometimes called childhood Alzheimer’s, is a rare neurovisceral lipid storage disease with progressive neurodegeneration leading to premature death. The disease is caused by loss-of-function mutations in the Npc1 or Npc2 gene which both result into lipid accumulation in the late endosomes and lysosomes. Since the disease presents with a broad heterogenous clinical spectrum, the involved disease mechanisms are still incompletely understood and this hampers finding an effective treatment. As NPC patients, who carry NPC1 mutations, have shown to share several pathological features with Alzheimer’s disease (AD) and we and others have previously shown that AD is associated with a dysfunctionality of the blood-cerebrospinal fluid (CSF) barrier located at choroid plexus, we investigated the functionality of this latter barrier in NPC1 pathology. Using NPC1–/– mice, we show that despite an increase in inflammatory gene expression in choroid plexus epithelial (CPE) cells, the blood-CSF barrier integrity is not dramatically affected. Interestingly, we did observe a massive increase in autophagosomes in CPE cells and enlarged extracellular vesicles (EVs) in CSF upon NPC1 pathology. Additionally, we revealed that these EVs exert toxic effects on brain tissue, in vitro as well as in vivo. Moreover, we observed that EVs derived from the supernatant of NPC1–/– choroid plexus explants are able to induce typical brain pathology characteristics of NPC1–/–, more specifically microgliosis and astrogliosis. Taken together, our data reveal for the first time that the choroid plexus and CSF EVs might play a role in the brain-related pathogenesis of NPC1.
Highlights
Niemann-Pick disease type C (NPC) is a highly heterogeneous rare lipid storage disorder with an incidence estimated at about 1 in 100,000 individuals (Vanier, 2010)
The choroid plexus is believed to be an entry gate of leukocytes into the brain (Demeestere et al, 2015). In this regard we looked into the inflammatory state of the choroid plexus of NPC1 diseased mice at intermediate and end-stage of the disease (Figure 1A)
Pathology within the central nervous system (CNS) is a feature of most lysosomal storage diseases, probably because neurons are uniquely vulnerable to perturbation of normal lysosomal activity
Summary
Niemann-Pick disease type C (NPC) is a highly heterogeneous rare lipid storage disorder with an incidence estimated at about 1 in 100,000 individuals (Vanier, 2010). The disease is characterized by the accumulation of unesterified cholesterol and other lipids in the late endosomes and lysosomes (LE/Lys) and is caused by loss-of-function mutation in the Npc (95%) or Npc (5%) gene. The corresponding proteins yield deficient function in the binding and transport of intracellular. Choroid Plexus in Niemann-Pick Disease cholesterol, resulting in cholesterol accumulation within LE/Lys. As every cell is affected by an impaired cholesterol trafficking mechanism, NPC pathology affects basically every organ. Some organs show worse clinical features than others. The liver, spleen and lungs and the brain are heavily affected
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