Involvement of the Choroid Plexus in the Pathogenesis of Niemann-Pick Disease Type C

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.

The type I interferon antiviral response in the choroid plexus and the cognitive risk in COVID-19

“…18 ). Of note, however, bulk RNA-sequencing analyses of the choroid plexus transcriptome showed enhanced type I IFN signaling also under noninfectious conditions, such as normal aging 1 and neurodegenerative diseases of diverse etiology that are also associated with reduced cognitive ability in mice and humans, such as Alzheimer's disease 2,3 and Niemann-Pick's disease type C 4 . In particular, type I IFN signaling at the choroid plexus is associated with cognitive impairment and reduced hippocampal neurogenesis in aged mice 1 .…”

“…This interface is responsible for allowing passage of nutrients and other molecules that the brain needs for its lifelong health, while preventing entry of microorganisms such as viruses and bacteria to the brain. Here, based on the understanding that this anatomical barrier can express an antiviral immunological signature under virus-free conditions [1][2][3][4] , we propose that although the choroid plexus is endowed with an active protective role that can destroy viruses before they infect the brain, its defensive activities could also have negative consequences for the brain if not fully resolved in a timely manner. Multiple reports document cases of broad-spectrum neurological symptoms in individuals with COVID-19 after recovery, including persistent cognitive impairment 5,6 .…”

NPC1 Deficiency Contributes to Autophagy-Dependent Ferritinophagy in HEI-OC1 Auditory Cells

“…NPCD is mainly characterized by cholesterol accumulation, and it affects multiple organelles such as the central nervous system (CNS), visceral organelles, and auditory system (King, 2014a;Wheeler and Sillence, 2020). Current research show more interests on the former (Vanier, 2010;Santos-Lozano et al, 2015;Balboa et al, 2021;Van Hoecke et al, 2021), but fewer studies have focused on the effect of NPCD related to genetic hearing loss and the molecular mechanism has not been fully understood to date.…”

Recommendations for reproducibility of cerebrospinal fluid extracellular vesicle studies

“…The size profile and number concentration of CSF EV subtypes and/or particles may relate to disease states. A relatively consistent finding reported across studies and species is a change in the median CSF EV and/or particle size and concentration with aging by NTA (Tietje et al., 2014), and with diseases including PD by NTA and bead‐based FC (Vacchi et al., 2021), multiple sclerosis by FC (Pieragostino et al., 2018; Verderio et al., 2012), Niemann‐Picks disease by SP‐IRIS (Van Hoecke et al., 2021), herpes simplex encephalitis by NTA (Li et al., 2022), post‐traumatic brain injury by NTA (Kuharić et al., 2019; Manek et al., 2018) and AD by NTA and SP‐IRIS (Vandendriessche et al., 2021). Single‐particle analysis of CSF EVs has been performed with both fractionated and unfractionated CSF (for individual references see Table S2).…”

“…There is also evidence that microglial small EVs facilitate and contribute to alpha‐synuclein transmission in PD (Crotti et al., 2019; Guo et al., 2020), highlighting potential EV roles in disease pathophysiology. Other pathological functions of CSF EVs include inflammatory responses mediated by choroid plexus derived‐EVs, which contribute to cognitive decline in two mouse models of AD (Vandendriessche et al., 2021) and induce microgliosis and astrogliosis in the Niemann‐Pick's disease mouse model of neurodegeneration (Van Hoecke et al., 2021). In glioblastoma patients, CSF EVs are implicated in immune evasion and immunosuppressive mechanisms (Wang et al., 2020).…”