MICROGLIAL ACTIVATION PATHWAYS--REGULATION BY APOE

小胶质细胞活化与大多数类型的神经病理学有关， 最近的证据表明，小胶质细胞的激活可能有助于 导致某些神经元死亡。小胶质细胞激活导致 混合神经元/神经胶质培养物中的选择性神经元群体。 的 参与产生细胞毒素的小胶质细胞通路，特别是 对神经元的选择性，仍然缺乏表征。 酵母聚糖a 经典的吞噬巨噬细胞激活剂，是一种更具神经毒性的 脂多糖（LPS）是一种可溶性内毒素， 通常用于激活小胶质细胞。 蛋白激酶C活化 似乎可以解释酵母多糖相对于 到LPS。 载脂蛋白E（apoE），一种胶质衍生因子， 脑损伤后产量急剧增加，最近被 显示抑制小胶质细胞活化。 一个人类apoE等位基因，apoE 4， 增加患老年痴呆症的风险，相对于 常见等位基因apoE 2和apoE 3。 越来越多的证据表明apoE 4 随着严重程度的增加和预后的恶化， 神经病理学也是。 据报道，ApoE 4比ApoE 2更有效。 或3抑制至少某些形式的小胶质细胞活化。 我们 建议使用来自不表达apoE的转基因小鼠的细胞培养物， 鼠apoE、人apoE 2、3或4，以研究apoE在哪些步骤 抑制小胶质细胞的激活， 人apoE亚型的作用。 特别是，我们将确定 apoE亚型是否优先抑制对可溶性或 吞噬刺激，以及神经元特异性毒素的产生是否是 被任何内源性产生的apoE同种型选择性抑制。

Microglial activation is associated with most types of neuropathology, and recent evidence suggests that microglial activation may contribute to death of certain neurons. Microglial activation leads to death of selective populations of neurons in mixed neuronal/glial cultures. The microglial pathways involved in producing cytotoxins, particularly ones selective for neurons, remain poorly characterized. Zymosan, a classical phagocytosed macrophage activator, is a more neurotoxic microglial activator than lipopolysaccharide (LPS), a soluble endotoxin commonly used to activate microglia. Protein kinase C activation appears to account for the increased neurotoxicity of zymosan relative to LPS. Apolipoprotein E (apoE), a glial derived factor whose production increases dramatically after brain injury, has recently been shown to suppress microglial activation. One human apoE allele, apoE4, increases the risk of developing Alzheimers Disease relative to the more common alleles apoE2 and apoE3. Increasing evidence implicates apoE4 as increasing severity and worsening prognosis for other neuropathologies as well. ApoE4 is reportedly less effective than apoE2 or 3 at suppressing at least some forms of microglial activation. We propose to use cell cultures from transgenic mice expressing no apoE, murine apoE, human apoE2, 3 or 4 to investigate at which steps apoE inhibits microglial activation and whether there is a differential effect of the human apoE isoforms. In particular, we will determine whether apoE isoforms preferentially inhibit responses to soluble or phagocytosed stimuli, and whether neuron-specific toxin production is selectively inhibited by any of the endogenously produced apoE isoforms.