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NPC is inherited in an autosomal recessive pattern from mutations in <jats:italic>NPC1<\/jats:italic> or <jats:italic>NPC2<\/jats:italic> 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 <jats:italic>Npc1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> 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-\u03b3-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 <jats:italic>Npc1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>We carried out genome-wide comparative transcriptome analyses of pre-symptomatic <jats:italic>Npc1<\/jats:italic><jats:sup><jats:italic>+\/+<\/jats:italic><\/jats:sup><jats:italic>\/App<\/jats:italic><jats:sup><jats:italic>+\/+<\/jats:italic><\/jats:sup>, <jats:italic>Npc1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup><jats:italic>\/App<\/jats:italic><jats:sup><jats:italic>+\/+<\/jats:italic><\/jats:sup>, <jats:italic>Npc1<\/jats:italic><jats:sup><jats:italic>+\/+<\/jats:italic><\/jats:sup><jats:italic>\/App<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>, and <jats:italic>Npc1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup><jats:italic>\/App<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mouse cerebella to identify biological pathways in the NPC brain further affected by the loss of APP. <jats:italic>Gene Set Enrichment Analysis<\/jats:italic> and <jats:italic>Ingenuity Pathway Analysis<\/jats:italic> 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.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>Expression of IFN-\u03b3- and IFN-\u03b1-responsive genes in pre-symptomatic <jats:italic>Npc1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup><jats:italic>\/App<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> cerebella is upregulated compared with <jats:italic>Npc1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup><jats:italic>\/App<\/jats:italic><jats:sup><jats:italic>+\/+<\/jats:italic><\/jats:sup> 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-\u03b3, as well as RANTES\/CCL5, eotaxin\/CCL11 and IL-10, prior to symptomatic onset in <jats:italic>Npc1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup><jats:italic>\/App<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> cerebella, compared with <jats:italic>Npc1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup><jats:italic>\/App<\/jats:italic><jats:sup><jats:italic>+\/+<\/jats:italic><\/jats:sup>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 <jats:italic>Npc1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup><jats:italic>\/App<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> cerebella.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Conclusions<\/jats:title>\n<jats:p>Loss 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.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s12974-019-1663-5","type":"journal-article","created":{"date-parts":[[2019,12,17]],"date-time":"2019-12-17T14:02:31Z","timestamp":1576591351000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Loss of amyloid precursor protein exacerbates early inflammation in Niemann-Pick disease type C"],"prefix":"10.1186","volume":"16","author":[{"given":"Samuel D.","family":"Shin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karina","family":"Mayagoitia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorraine","family":"Siebold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marsilio","family":"Rubini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher G.","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise L.","family":"Bellinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6369-4586","authenticated-orcid":false,"given":"Salvador","family":"Soriano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,12,17]]},"reference":[{"key":"1663_CR1","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/1750-1172-5-16","volume":"5","author":"MT Vanier","year":"2010","unstructured":"Vanier MT. 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