Choroid plexus genes for CSF production and brain homeostasis are altered in Alzheimer's disease
Choroid plexus genes for CSF production and brain homeostasis are altered in Alzheimer's disease
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DOI：
10.1186/s12987-018-0120-7
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发表时间：
2018-12-12
影响因子：
7.3
通讯作者：
Silverberg, Gerald D.
中科院分区：
文献类型：
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作者：
Kant, Shawn;Stopa, Edward G.;Silverberg, Gerald D.
背景脉络丛（CP）和脑脊液（CSF）产生的作用在阿尔茨海默病（AD）研究中引起了越来越多的关注。具体来说，研究记录了中度至重度 AD 中脑脊液的产生和周转显着减少。此外，脑脊液功能和脑脊液周转率的降低会导致有毒代谢物的清除受损，可能会促进神经炎症，并可能在 AD 进展过程中促进神经元死亡。我们分析了 AD 中与对照受试者相比的 CP 基因表达，特别考虑了那些与 CSF 产生和 CP 结构完整性有关的基因。方法挖掘 Brown-Merck 基因表达综合 (GEO) 数据库（CP 转录本）来检查 AD 中与对照受试者相比基因表达的变化，重点关注被认为在 CSF 产生中发挥作用的各种基因。具体来说，选择编码 CP 上皮 (CPE) 中离子转运蛋白和相关酶（例如 Na-K-ATP 酶和碳酸酐酶）、水通道蛋白、线粒体转运蛋白/酶、血脑脊液屏障 (BCSFB) 稳定蛋白和促炎介质的基因进行研究。使用t检验p值和GEO数据库的GEO2R特征进行倍数变化分析来分析数据。结果在AD CP中观察到多个基因的显着表达变化。这些包括离子转运蛋白（例如，溶质载体基因 SLC4A5，p=0.004）和相关酶表达（例如，碳酸酐酶 CA4，p=0.0001）的破坏，以及涉及 BCSFB 完整性的基因表达减少（例如，密蛋白 CLDN5，p=0.039）和线粒体 ATP 合成（例如，三磷酸腺苷） ATP5L，p=0.0004）。所有的变化都表明 AD 中血液-脑脊液界面的溶质运输受到破坏。促炎性基因（例如，白细胞介素 IL1RL1，p=0.00001）和潜在神经退行性基因（例如，淀粉样蛋白前体 APBA3，p=0.002）表达的增加也表明 CP 功能受到干扰。 结论 由于 AD-CP 中大量转录物表达的改变有助于解释 AD 中脑脊液生成的减少，这些发现代表了确定 AD 中新治疗靶点的第一步。
BackgroundThe roles of the choroid plexus (CP) and cerebrospinal fluid (CSF) production have drawn increasing attention in Alzheimer's disease (AD) research. Specifically, studies document markedly decreased CSF production and turnover in moderate-to-severe AD. Moreover, reduced CP function and CSF turnover lead to impaired clearance of toxic metabolites, likely promote neuroinflammation, and may facilitate neuronal death during AD progression. We analyzed CP gene expression in AD compared with control subjects, specifically considering those genes involved with CSF production and CP structural integrity.MethodsThe Brown-Merck Gene Expression Omnibus (GEO) database (CP transcripts) was mined to examine changes in gene expression in AD compared to controls with a focus on assorted genes thought to play a role in CSF production. Specifically, genes coding for ion transporters in CP epithelium (CPE) and associated enzymes like Na-K-ATPase and carbonic anhydrase, aquaporins, mitochondrial transporters/enzymes, blood-cerebrospinal fluid barrier (BCSFB) stability proteins, and pro-inflammatory mediators were selected for investigation. Data were analyzed using t test p-value and fold-change analysis conducted by the GEO2R feature of the GEO database.ResultsSignificant expression changes for several genes were observed in AD CP. These included disruptions to ion transporters (e.g., the solute carrier gene SLC4A5, p=0.004) and associated enzyme expressions (e.g., carbonic anhydrase CA4, p=0.0001), along with decreased expression of genes involved in BCSFB integrity (e.g., claudin CLDN5, p=0.039) and mitochondrial ATP synthesis (e.g., adenosine triphosphate ATP5L, p=0.0004). Together all changes point to disrupted solute transport at the blood-CSF interface in AD. Increased expression of pro-inflammatory (e.g., interleukin IL1RL1, p=0.00001) and potential neurodegenerative genes (e.g., amyloid precursor APBA3, p=0.002) also implicate disturbed CP function.ConclusionsBecause the altered expression of numerous transcripts in AD-CP help explain decreased CSF production in AD, these findings represent a first step towards identifying novel therapeutic targets in AD.