Apolipoprotein E-containing lipoproteins protect neurons from apoptosis via a signaling pathway involving low-density lipoprotein receptor-related protein-1
Apolipoprotein E-containing lipoproteins protect neurons from apoptosis via a signaling pathway involving low-density lipoprotein receptor-related protein-1
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DOI：
10.1523/jneurosci.5471-06.2007
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发表时间：
2007-02-21
影响因子：
5.3
通讯作者：
Vance, Jean E.
中科院分区：
文献类型：
--
作者：
Hayashi, Hideki;Campenot, Robert B.;Vance, Jean E.
含载脂蛋白E（apoE）的脂蛋白（lipoprotein，LP）由神经胶质细胞分泌，在中枢神经系统脂质平衡中起重要作用。胶质细胞衍生的LP还促进突触发生并刺激CNS神经元的轴突生长。在这里，我们提供的证据表明，胶质细胞衍生的脂多糖保护中枢神经系统神经元凋亡的受体介导的信号通路。载脂蛋白E3的保护作用大于载脂蛋白E4，载脂蛋白E4的表达是阿尔茨海默病的危险因素。脂多糖的抗凋亡作用需要载脂蛋白E与脂质的结合，但不需要胆固醇。单独脂质或含apoA 1或apoJ的脂蛋白不能阻止细胞凋亡。脂蛋白与低密度脂蛋白受体相关蛋白（LRP）结合后，神经元凋亡的预防开始，LRP是低密度脂蛋白受体家族的多功能受体。我们发现，通过用受体相关蛋白或抗LRP抗体处理神经元或通过LRP基因沉默实验抑制LRP激活，降低了LPs的保护作用。此外，另一种LRP配体，α 2-巨球蛋白，也保护神经元免于凋亡。在与LRP结合后，LP启动涉及蛋白激酶C δ的活化和糖原合成酶激酶-3 β的失活的信号传导途径。这些发现表明了使用神经胶质脂蛋白或LRP信号通路的激活剂治疗神经退行性疾病如阿尔茨海默病的潜力。
Apolipoprotein E (apoE)-containing lipoproteins (LPs) are secreted by glia and play important roles in lipid homeostasis in the CNS. Glia-derived LPs also promote synaptogenesis and stimulate axon growth of CNS neurons. Here, we provide evidence that glia-derived LPs protect CNS neurons from apoptosis by a receptor-mediated signaling pathway. The protective effect was greater for apolipoprotein E3 than for apolipoprotein E4, the expression of which is a risk factor for Alzheimer's disease. The anti-apoptotic effect of LPs required the association of apolipoprotein E with lipids but did not require cholesterol. Apoptosis was not prevented by lipids alone or by apoA1- or apoJ-containing lipoproteins. The prevention of neuronal apoptosis was initiated after the binding of LPs to the low-density lipoprotein receptor-related protein (LRP), a multifunctional receptor of the low-density lipoprotein receptor family. We showed that inhibition of LRP activation, by treatment of neurons with receptor-associated protein or anti- LRP antibodies, or by LRP gene-silencing experiments, reduced the protective effect of LPs. Furthermore, another LRP ligand, alpha 2-macroglobulin, also protected the neurons from apoptosis. After binding to LRP, LPs initiate a signaling pathway that involves activation of protein kinase C delta and inactivation of glycogen synthase kinase-3 beta. These findings indicate the potential for using glial lipoproteins or an activator of the LRP signaling pathway for treatment for neurodegenerative disorders such as Alzheimer's disease.