BACKGROUND Niemann-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. METHODS We 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. RESULTS Expression 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. CONCLUSIONS 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.

中文翻译：

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淀粉样前体蛋白的丢失加剧了C型尼曼-皮克病的早期炎症。

背景技术C型尼曼-皮克病（NPC）是进行性神经退行性疾病，导致早期死亡。NPC以常染色体隐性方式从NPC1或NPC2基因的突变中遗传。鼻咽癌的病因定义不清。在这方面，神经炎症发生在疾病的早期，我们最近在症状前的Npc1-/-小鼠中发现了干扰素信号传导的非典型模式，具有小胶质细胞激活，抗病毒反应，抗原呈递细胞激活以及激活和激活。 T淋巴细胞的趋化性是影响病理通路的关键。此外，IP-10 / CXCL10（一种有效的IFN-γ应答细胞因子）被确定为这些早期炎症异常的潜在介体。这里，我们询问淀粉样蛋白前体蛋白（APP）功能的丧失是否会加剧这种异常信号传导，后者是已知会缩短寿命并加速Npc1-/-小鼠的神经变性的功能。方法我们对症状前的Npc1 + / + / App + / +，Npc1-/-/ App + / +，Npc1 + / + / + / App-/-和Npc1-/-/ App-/-进行了全基因组比较转录组分析小鼠小脑以确定NPC脑中的生物途径进一步受到APP丢失的影响。基因集富集分析和独创性途径分析被用于高差异表达基因的分子作图和功能性上游途径分析。我们同时测量了这些小鼠小脑中32种炎性细胞因子和趋化因子的表达，包括在我们的全基因组分析中确定的表达。最后，我们使用免疫组化方法来测量小脑中的T细胞浸润。结果与Npc1-/-// App + / +小鼠相比，有症状的Npc1-/-/ App-/-小脑中IFN-γ-和IFN-α响应基因的表达上调，加剧了小胶质细胞激活的异常调节，抗病毒反应，抗原呈递细胞的激活以及NPC脑中存在的T淋巴细胞激活和趋化途径。多重蛋白分析进一步显示，在Npc1-/-/ App-发病之前，IP-10 / CXCL10（一种有效的IFN-γ下游效应物）以及RANTES / CCL5，eotaxin / CCL11和IL-10的表达升高。 /-小脑，与Npc1-/-/ App + / +小鼠相比。在末期疾病阶段，APP的丧失导致所评估的绝大多数细胞因子的多效性差异表达。最后，我们提供了Npc1-/-// App-/-小脑中T细胞浸润的证据。结论APP的丧失加重了在NPC脑部症状发作之前发生的致病性神经炎症。这些发现为APP在中枢神经系统中作为细胞保护调节剂的功能提供了新的亮点，提供了针对NPC的潜在循证疗法。