Neurotoxicity from innate immune response is greatest with targeted replacement of ε4 allele of apolipoprotein E gene and is mediated by microglial p38MAPK
Neurotoxicity from innate immune response is greatest with targeted replacement of ε4 allele of apolipoprotein E gene and is mediated by microglial p38MAPK
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DOI：
10.1096/fj.05-5423fje
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发表时间：
2006-02-01
期刊：
影响因子：
4.8
通讯作者：
Montine, Thomas J.
中科院分区：
文献类型：
--
作者：
Maezawa, Izumi;Nivison, Mary;Montine, Thomas J.
APOE等位基因的遗传与几种神经退行性疾病的不同临床结局相关，这些疾病与脑中的先天免疫反应相关。我们测试了以下假设：不同APOE等位基因的遗传将显着调节神经胶质先天免疫反应引起的神经毒性。我们首先使用野生型（wt）鼠神经元和神经胶质细胞的解离培养物，这些神经元和神经胶质细胞来源于具有靶向替代（TR）的APOE等位基因的小鼠。我们的研究结果表明，绝大多数旁观者的损害WT神经元来自小胶质细胞是最大的TR APOE4胶质细胞，中间TR APOE3胶质细胞，TR APOE2胶质细胞和之前可检测的NO分泌最少。小胶质细胞p38 MAPK依赖性细胞因子分泌遵循TR APOE依赖性的类似模式。在海马切片培养中，先天性免疫激活具有类似的TR APOE依赖性模式，并在TR APOE 4和TR APOE 3中产生突触后神经元损伤，但在TR APOE 2培养物中不产生p38 MAPK依赖性神经元损伤。这些发现提示了一种新的机制，不同APOE等位基因的遗传可能会影响与小胶质细胞先天免疫反应相关的神经退行性疾病的结局。
Inheritance of APOE alleles is associated with varying clinical outcomes in several neurodegenerative diseases that are associated with innate immune response in brain. We tested the hypothesis that inheritance of different APOE alleles would significantly modulate neurotoxicity arising from glial innate immune response. We first used dissociated cultures of wild-type (wt) murine neurons and glia derived from mice with targeted replacement (TR) of the epsilon 2, epsilon 3, or, epsilon 4 APOE allele. Our results showed that the vast majority of bystander damage to wt neurons derived from microglia was greatest with TR APOE4 glia, intermediate from TR APOE3 glia, and least from TR APOE2 glia and preceded detectable NO secretion. Microglial p38MAPK-dependent cytokine secretion followed a similar pattern of TR APOE dependence. In hippocampal slice cultures, innate immune activation had a similar pattern of TR APOE-dependence and produced postsynaptic neuronal damage in TR APOE4 and TR APOE3 but not TR APOE2 cultures that was p38MAPK dependent. These findings suggest a new mechanism by which inheritance of different APOE alleles may influence the outcome of neurodegenerative diseases associated with microglial innate immune response.