Cellular Source of Apolipoprotein E4 Determines Neuronal Susceptibility to Excitotoxic Injury in Transgenic Mice
Cellular Source of Apolipoprotein E4 Determines Neuronal Susceptibility to Excitotoxic Injury in Transgenic Mice
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DOI：
10.2353/ajpath.2010.090973
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发表时间：
2010-08-01
影响因子：
6
通讯作者：
Mucke, Lennart
中科院分区：
文献类型：
--
作者：
Buttini, Manuel;Masliah, Eliezer;Mucke, Lennart
脂质转运蛋白载脂蛋白E（apoE）在大脑中大量表达。其在人类中的主要异构体为apoE2、apoE3和apoE4。ApoE4是已知的阿尔茨海默病的主要遗传风险因素，并且也参与多种其他神经系统疾病的发病机制。在中枢神经系统中，apoE由神经胶质细胞和神经元合成，但细胞来源是否影响其生物学活性尚不清楚。为了解决这一问题，我们通过在星形胶质细胞或神经元中表达人apoE异构体的转基因Apoe敲除小鼠中全身注射海人酸诱导兴奋性毒性损伤。无论其细胞来源如何，apoE3的表达都能保护神经元突触和树突免受在apoE缺陷小鼠中所见的兴奋性毒性。先前已表明在体外具有有害作用的星形胶质细胞源性apoE4在体内与apoE3一样具有兴奋保护作用。相反，apoE4的神经元表达没有保护作用，并且在兴奋性毒性刺激后导致皮质神经元丢失，这表明神经元apoE4促进兴奋性毒性细胞死亡。因此，星形胶质细胞（兴奋保护）和神经元（神经毒性）apoE4表达之间的失衡可能会增加对涉及兴奋性毒性机制的多种神经系统疾病的易感性。（《美国病理学杂志》2010年，177：563 - 569；DOI：10.2353/ajpath.2010.090973）
The lipid transport protein apolipoprotein E (apoE) is abundantly expressed in the brain. Its main isoforms in humans are apoE2, apoE3, and apoE4. ApoE4 is the major known genetic risk factor for Alzheimer's disease and also contributes to the pathogenesis of various other neurological conditions. In the central nervous system, apoE is synthesized by glial cells and neurons, but it is unclear whether the cellular source affects its biological activities. To address this issue, we induced excitotoxic injury by systemic kainic acid injection in transgenic Apoe knockout mice expressing human apoE isoforrns in astrocytes or neurons. Regardless of its cellular source, apoE3 expression protected neuronal synapses and dendrites against the excitotoxicity seen in apoE-deficient mice. Astrocyte-derived apoE4, which has previously been shown to have detrimental effects in vitro, was as excitoprotective as apoE3 in vivo. In contrast, neuronal expression of apoE4 was not protective and resulted in loss of cortical neurons after excitotoxic challenge, indicating that neuronal apoE4 promotes excitotoxic cell death. Thus, an imbalance between astrocytic (excitoprotective) and neuronal (neurotoxic) apoE4 expression may increase susceptibility to diverse neurological diseases involving excitotoxic mechanisms. (Am J Pathol 2010, 177:563-569; DOI: 10.2353/ajpath.2010.090973)