Functional variability in butyrylcholinesterase activity regulates intrathecal cytokine and astroglial biomarker profiles in patients with Alzheimer's disease
Functional variability in butyrylcholinesterase activity regulates intrathecal cytokine and astroglial biomarker profiles in patients with Alzheimer's disease
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DOI：
10.1016/j.neurobiolaging.2013.04.027
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发表时间：
2013-11-01
影响因子：
4.2
通讯作者：
Nordberg, Agneta
中科院分区：
文献类型：
--
作者：
Darreh-Shori, Taher;Vijayaraghavan, Swetha;Nordberg, Agneta
丁酰胆碱酯酶（BuChE）活性与阿尔茨海默病脑中活化的星形胶质细胞相关。BuChE-K变体表现出降低30%-60%的乙酰胆碱（ACh）水解能力。考虑到越来越多的证据表明ACh的免疫调节作用，我们研究了BuChE的遗传异质性是否影响炎症和胆碱能神经胶质功能的脑脊液（CSF）生物标志物。阿尔茨海默病患者（n = 179）进行BCHE-K基因分型。对CSF和/或血浆进行蛋白质组学和酶分析。BuChE基因型与CSF中胶质细胞酸性蛋白、S100 B、白细胞介素-1 β和肿瘤坏死因子（TNF）-α的不同水平有关。与BCHE-K携带者相比，BCHE-K非携带者显示出高100%-150%的胶质细胞酸性蛋白和高64%-110%的S100 B，相比之下，与非携带者相比，BCHE-K携带者具有高40%-80%的IL-1b和高21%-27%的TNF-α。高水平的CSF BuChE酶表型也与较高的CSF星形胶质细胞标志物水平和先天补体系统的几个因子显著相关，但与较低的促炎细胞因子水平相关。这些个体还显示出有益的临床前和临床发现，如高脑葡萄糖利用率、低β-淀粉样蛋白负荷和临床症状进展不太严重。对人星形胶质细胞的体外分析证实了星形胶质细胞对TNF-α和ACh的反应中涉及受调节的BuChE状态。在大鼠神经损伤诱导的神经炎症模型中的组织化学分析显示，BuChE免疫标记位点附近的星形胶质细胞集中。总之，这些结果表明，BuChE酶活性在调节胆碱能神经胶质细胞的内在炎症和活性中起着重要作用，这可能具有临床意义。星形胶质细胞标记物和炎性细胞因子之间的分离表明，星形胶质细胞功能的适当激活和维持是有益的反应，而不是疾病驱动机制。需要进一步的研究来探索操纵BuChE活性或星形胶质细胞功能状态的治疗潜力。(C)2013 Elsevier Inc. All rights reserved.
Butyrylcholinesterase (BuChE) activity is associated with activated astrocytes in Alzheimer's disease brain. The BuChE-K variant exhibits 30%-60% reduced acetylcholine (ACh) hydrolyzing capacity. Considering the increasing evidence of an immune-regulatory role of ACh, we investigated if genetic heterogeneity in BuChE affects cerebrospinal fluid (CSF) biomarkers of inflammation and cholinoceptive glial function. Alzheimer's disease patients (n = 179) were BCHE-K-genotyped. Proteomic and enzymatic analyses were performed on CSF and/or plasma. BuChE genotype was linked with differential CSF levels of glial fibrillary acidic protein, S100B, interleukin-1 beta, and tumor necrosis factor (TNF)-alpha. BCHE-K noncarriers displayed 100%-150% higher glial fibrillary acidic protein and 64%-110% higher S100B than BCHE-K carriers, who, in contrast, had 40%-80% higher interleukin-1b and 21%-27% higher TNF-alpha compared with noncarriers. A high level of CSF BuChE enzymatic phenotype also significantly correlated with higher CSF levels of astroglial markers and several factors of the innate complement system, but lower levels of proinflammatory cytokines. These individuals also displayed beneficial paraclinical and clinical findings, such as high cerebral glucose utilization, low beta-amyloid load, and less severe progression of clinical symptoms. In vitro analysis on human astrocytes confirmed the involvement of a regulated BuChE status in the astroglial responses to TNF-alpha and ACh. Histochemical analysis in a rat model of nerve injury-induced neuroinflammation, showed focal assembly of astroglial cells in proximity of BuChE-immunolabeled sites. In conclusion, these results suggest that BuChE enzymatic activity plays an important role in regulating intrinsic inflammation and activity of cholinoceptive glial cells and that this might be of clinical relevance. The dissociation between astroglial markers and inflammatory cytokines indicates that a proper activation and maintenance of astroglial function is a beneficial response, rather than a disease-driving mechanism. Further studies are needed to explore the therapeutic potential of manipulating BuChE activity or astroglial functional status. (C) 2013 Elsevier Inc. All rights reserved.