Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Choju Medical Institute, Fukushimura Hospital, Toyohashi, 441-8124, Japan.
Proc Natl Acad Sci U S A. 2017 Apr 4;114(14):E2947-E2954. doi: 10.1073/pnas.1615036114. Epub 2017 Mar 20.
We previously showed that microglial keratan sulfate (KS) was induced in amyotrophic lateral sclerosis. However, the functional roles of the glycan and its synthetic enzyme in neurodegenerative diseases, such as Alzheimer's disease (AD), a progressive disorder, are unclear. In our study, KS modified with sialic acids having a molecular mass of 125-220 kDa and the carbohydrate sulfotransferase GlcNAc6ST1 were up-regulated in the brains of two transgenic mouse models (J20 and Tg2576) and the brains of patients with AD. GlcNAc6ST1-deficient J20 (J20/GlcNAc6ST1) mice demonstrated a complete absence of the microglial sialylated KS. J20/GlcNAc6ST1 primary microglia showed an increased level of amyloid-β phagocytosis and were hyperresponsive to interleukin 4, a potent antiinflammatory cytokine. Moreover, J20/GlcNAc6ST1 mice manifested reduced cerebral amyloid-β deposition. GlcNAc6ST1-synthesizing sialylated KS thus modulates AD pathology. Inhibition of KS synthesis by targeting GlcNAc6ST1 may therefore be beneficial for controlling AD pathogenesis.
我们之前曾表明，在肌萎缩侧索硬化症中诱导了小胶质细胞角鲨胺硫酸盐（KS）。然而，糖胺聚糖及其合成酶在神经退行性疾病（如阿尔茨海默病（AD））中的功能作用尚不清楚，AD 是一种进行性疾病。在我们的研究中，在两种转基因小鼠模型（J20 和 Tg2576）和 AD 患者的大脑中，带有 125-220 kDa 分子量的唾液酸修饰的 KS 和糖胺聚糖 6-O-磺基转移酶 1（GlcNAc6ST1）都被上调。GlcNAc6ST1 缺陷型 J20（J20/GlcNAc6ST1）小鼠的小胶质细胞完全没有唾液酸化的 KS。J20/GlcNAc6ST1 原代小胶质细胞表现出更高水平的淀粉样β吞噬作用，并且对白细胞介素 4（一种有效的抗炎细胞因子）更敏感。此外，J20/GlcNAc6ST1 小鼠表现出脑内淀粉样-β沉积减少。因此，合成唾液酸 KS 的 GlcNAc6ST1 调节 AD 病理学。通过靶向 GlcNAc6ST1 抑制 KS 合成可能有助于控制 AD 的发病机制。
