HNK-1 Carrier Glycoproteins Are Decreased in the Alzheimer's Disease Brain
HNK-1 Carrier Glycoproteins Are Decreased in the Alzheimer's Disease Brain
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DOI：
10.1007/s12035-015-9644-x
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发表时间：
2017-01-01
影响因子：
5.1
通讯作者：
Saez-Valero, Javier
中科院分区：
文献类型：
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作者：
Garcia-Ayllon, Maria-Salud;Botella-Lopez, Arancha;Saez-Valero, Javier
人类自然杀伤剂 1 (HNK-1)，即 3-磺化葡萄糖醛酸，是细胞粘附的糖表位标记物，参与细胞-细胞和细胞-细胞外基质相互作用以及神经突生长。关于 HNK-1 聚糖在神经退行性疾病，尤其是阿尔茨海默病 (AD) 中的调节作用，人们知之甚少。在这项研究中，我们研究了 AD 中 HNK-1 载体糖蛋白水平的变化。我们证明，与非痴呆对照 (NDC) 的水平相比，从 AD 受试者额叶皮层提取的糖蛋白中 HNK-1 免疫反应性总体下降。使用 HNK-1 抗体对脑室死后和腰椎死前脑脊液进行免疫印迹表明 AD 和 NDC 样本中载体糖蛋白水平相似。 HNK-1载体糖蛋白的减少与参与糖表位合成的酶、β-1,4-半乳糖基转移酶(β 4GalT)、葡萄糖醛酸转移酶GlcAT-P和GlCAT-S或磺基转移酶HNK-1ST的信使RNA (mRNA)水平的变化并不平行。 Tg2576 转基因小鼠中淀粉样蛋白前体蛋白的过度表达以及用致淀粉样蛋白 A β 42 肽对 SH-SY5Y 神经母细胞瘤细胞进行体外处理导致大脑和细胞提取物中 HNK-1 免疫反应性水平降低，而在培养基中检测到的可溶性 HNK-1 糖蛋白水平不受 A β 处理的影响。 HNK-1 水平在 Tg-VLW 小鼠（突变型过度磷酸化 tau 模型）的脑提取物中以及在过度表达过度磷酸化野生型 tau 的 SH-SY5Y 细胞中不受影响。这些结果提供证据表明，AD 受试者大脑中 HNK-1 载体糖型的细胞水平降低，可能是受到 β-淀粉样蛋白的影响。
The human natural killer-1 (HNK-1), 3-sulfonated glucuronic acid, is a glycoepitope marker of cell adhesion that participates in cell-cell and cell-extracellular matrix interactions and in neurite growth. Very little is known about the regulation of the HNK-1 glycan in neurodegenerative disease, particularly in Alzheimer's disease (AD). In this study, we investigate changes in the levels of HNK-1 carrier glycoproteins in AD. We demonstrate an overall decrease in HNK-1 immunoreactivity in glycoproteins extracted from the frontal cortex of AD subjects, compared with levels from non-demented controls (NDC). Immunoblotting of ventricular post-mortem and lumbar ante-mortem cerebrospinal fluid with HNK-1 antibodies indicate similar levels of carrier glycoproteins in AD and NDC samples. Decrease in HNK-1 carrier glycoproteins were not paralleled by changes in messenger RNA (mRNA) levels of the enzymes involved in the synthesis of the glycoepitope, beta-1,4-galactosyltransferase (beta 4GalT), glucuronyltransferases GlcAT-P and GlcAT-S, or sulfotransferase HNK-1ST. Over-expression of amyloid precursor protein in Tg2576 transgenic mice and in vitro treatment of SH-SY5Y neuroblastoma cells with the amyloidogenic A beta 42 peptide resulted in a decrease in HNK-1 immunoreactivity levels in brain and cellular extracts, whereas the levels of soluble HNK-1 glycoproteins detected in culture media were not affected by A beta treatment. HNK-1 levels remain unaffected in the brain extracts of Tg-VLW mice, a model of mutant hyperphosphorylated tau, and in SH-SY5Y cells over-expressing hyperphosphorylated wild-type tau. These results provide evidence that cellular levels of HNK-1 carrier glycoforms are decreased in the brain of AD subjects, probably influenced by the beta-amyloid protein.