Yao Z-X, Han Z, Xu J, Greeson J, Lecanu L, Papadopoulos V
Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC 20057, USA.
Neuroscience. 2007 Aug 24;148(2):441-53. doi: 10.1016/j.neuroscience.2007.06.013. Epub 2007 Aug 3.
Recently, we have shown that 22R-hydroxycholesterol, a steroid intermediate in the pathway of pregnenolone formation from cholesterol, is present at lower levels in Alzheimer's disease (AD) hippocampus and frontal cortex tissue specimens than in age-matched controls, and that this substance protects against cell death induced by amyloid beta-peptide in both rat sympathetic nerve pheochromocytoma (PC12) and differentiated human Ntera2/D1 teratocarcinoma neurons. Herein we report that 22R-hydroxycholesterol inhibits the proliferation of human Ntera2/D1 teratocarcinoma precursor cells (NT2) and induces these cells to differentiate into "neuron-like" or "astrocyte-like" cells. 22R-Hydroxycholesterol-induced differentiation of NT2 cells is associated with increases in the expression of neurofilament protein NF200, the cytoskeletal proteins microtubule-associated protein type II (MAP2) a and MAP2b, glial fibrillary acidic protein (GFAP) and glial cell line-derived neurotrophic factor receptor-alpha 2 (GFRalpha2). These effects of 22R-hydroxycholesterol are considered to be stereospecific because its enantiomer 22S-hydroxycholesterol and other steroids failed to induce differentiation of NT2 cells. 22R-Hydroxycholesterol was found to lack specific binding for numerous receptors, including all steroid receptors tested. However, using a cholesterol protein binding blot assay we demonstrated the presence of a 22R-hydroxycholesterol-binding protein in NT2 cells distinct from the human oxysterol receptors liver X receptor LXRalpha and beta.
最近，我们发现，22R-羟基胆固醇作为从胆固醇生成孕烯醇酮途径中的一种甾体中间体，在阿尔茨海默病（AD）海马体和额叶皮质组织标本中的含量低于年龄匹配的对照，并且该物质可保护大鼠交感神经嗜铬细胞瘤（PC12）和分化的人Ntera2/D1畸胎癌细胞免受β-淀粉样肽诱导的细胞死亡。在此我们报告，22R-羟基胆固醇可抑制人Ntera2/D1畸胎癌前体细胞（NT2）的增殖，并诱导这些细胞分化为“神经元样”或“星形胶质细胞样”细胞。22R-羟基胆固醇诱导的NT2细胞分化与神经丝蛋白NF200、细胞骨架蛋白微管相关蛋白II型（MAP2）a和MAP2b、胶质纤维酸性蛋白（GFAP）以及胶质细胞源性神经营养因子受体α2（GFRalpha2）表达的增加有关。22R-羟基胆固醇的这些作用被认为具有立体特异性，因为其对映体22S-羟基胆固醇和其他甾体未能诱导NT2细胞分化。发现22R-羟基胆固醇对众多受体缺乏特异性结合，包括所有测试的甾体受体。然而，使用胆固醇蛋白结合印迹分析，我们证明了NT2细胞中存在一种与人类氧化甾醇受体肝X受体LXRα和β不同的22R-羟基胆固醇结合蛋白。
