Loss of amyloid precursor protein exacerbates early inflammation in Niemann-Pick disease type C

Abstract

BackgroundNiemann-Pick disease type C (NPC) is a progressive neurodegenerative condition that results in early fatality. NPC is inherited in an autosomal recessive pattern from mutations in NPC1 or NPC2 genes. The etiology of NPC is poorly defined. In that regard, neuroinflammation occurs early in the disease and we have recently unveiled an atypical pattern of interferon signaling in pre-symptomatic Npc1−/− mice, with microglial activation, anti-viral response, activation of antigen-presenting cells, and activation and chemotaxis of T lymphocytes as the key affected pathologic pathways. Furthermore, IP-10/CXCL10, a potent IFN-γ-responsive cytokine, was identified as the potential mediator of these early inflammatory abnormalities. Here, we asked whether this aberrant signaling may be exacerbated by the loss of amyloid precursor protein (APP) function, a loss known to shorten lifespan and accelerate neurodegeneration in Npc1−/− mice.MethodsWe carried out genome-wide comparative transcriptome analyses of pre-symptomatic Npc1+/+/App+/+, Npc1−/−/App+/+, Npc1+/+/App−/−, and Npc1−/−/App−/− mouse cerebella to identify biological pathways in the NPC brain further affected by the loss of APP. Gene Set Enrichment Analysis and Ingenuity Pathway Analysis were utilized for molecular mapping and functional upstream pathway analyses of highly differentially expressed genes. We simultaneously measured the expression of 32 inflammatory cytokines and chemokines in the cerebella from these mice, including those identified in our genome-wide analyses. Finally, we used immunohistochemistry to measure T cell infiltration in the cerebellum.ResultsExpression of IFN-γ- and IFN-α-responsive genes in pre-symptomatic Npc1−/−/App−/− cerebella is upregulated compared with Npc1−/−/App+/+ mice, compounding the dysregulation of microglial activation, anti-viral response, activation of antigen-presenting cells, and T-lymphocyte activation and chemotaxis pathways present in the NPC brain. Multiplex protein analysis further showed elevated expression of IP-10/CXCL10, a potent downstream effector of IFN-γ, as well as RANTES/CCL5, eotaxin/CCL11 and IL-10, prior to symptomatic onset in Npc1−/−/App−/− cerebella, compared with Npc1−/−/App+/+mice. In the terminal disease stage, loss of APP caused pleiotropic differential expression of the vast majority of cytokines evaluated. Finally, we present evidence of T cell infiltration in Npc1−/−/App−/− cerebella.ConclusionsLoss of APP exacerbates the pathogenic neuroinflammation that occurs prior to symptomatic onset in the NPC brain. These findings shed new light on the function of APP as a cytoprotective modulator in the CNS, offering potential evidence-based therapies against NPC.

Serum Cytokine Profile, Beta-Hexosaminidase A Enzymatic Activity and GM2 Ganglioside Levels in the Plasma of a Tay-Sachs Disease Patient after Cord Blood Cell Transplantation and Curcumin Administration: A Case Report

“…IP-10 is a chemokine involved in the attraction of immune cells at inflammation sites [70], and IP-10 levels are frequently elevated during CNS infection [71]. High levels of IP-10 are associated with some LSDs [64,72,73]. Our data and other studies suggest that curcumin suppresses the expression of IP-10 [74,75], which could mean that it may help to reduce inflammation.…”

“…As mentioned earlier, elevated levels of eotaxin correlate with a number of nervous system disorders. To summarize, eotaxin is elevated in the cerebellum of model mice of Niemann-Pick type C (NPC) [64], is negatively correlated with gray matter in patients older than 60 years with late-life major depression [65] and is possibly associated with the loss of dopaminergic neurons in patients with Parkinson's disease [66]. In a mouse model of allergic asthma, it was shown that treatment with curcumin leads to suppression of the expression of many inflammatory cytokines, including eotaxin [67].…”

Penetrating Ballistic-Like Brain Injury Leads to MicroRNA Dysregulation, BACE1 Upregulation, and Amyloid Precursor Protein Loss in Lesioned Rat Brain Tissues

“…However, widespread protein and brain tissue degradation is a consistent feature of open skull, severe TBI models per observation of apoptosis (Brophy et al, 2009;Cartagena et al, 2013), as well as axonal fiber and cellular degeneration (Brophy et al, 2009;Shear et al, 2009;Gajavelli et al, 2015). A novel aspect of this model is presented by this study, which found that miRNAs affected by PBBI over time collectively mapped to APP processing, a key feature of neurodegeneration (Roberts et al, 1994;Nguyen, 2019;Shin et al, 2019), that overlaps the timeframe of widespread degradation in this model.…”

Understanding and Treating Niemann–Pick Type C Disease: Models Matter

“…In mice, the outcome of a given mutation varies with the genetic background of strains [37,135,[215][216][217][218]. Numerous double mutant mice have been created to test whether and how specific candidate genes impact the disease [163,173,177,190,191,[219][220][221][222][223][224][225][226][227][228][229][230][231][232][233][234][235]. Sex-dependent differences in behavior [236], life span [37,134], and responses to immune activation [237] and to potential therapies [171,238] were reported in some NPC1 mutant mice, raising the question of whether sex is a modifying factor in NPC disease [37] as in other cholesterol-related pathologies [239][240][241][242] and normal cholesterol homeostasis [243,244].…”