Low Density Lipoprotein Receptor-related Protein 1 Promotes Anti-apoptotic Signaling in Neurons by Activating Akt Survival Pathway
Low Density Lipoprotein Receptor-related Protein 1 Promotes Anti-apoptotic Signaling in Neurons by Activating Akt Survival Pathway
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DOI：
10.1074/jbc.m109.021030
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发表时间：
2009-12-04
影响因子：
4.8
通讯作者：
Bu, Guojun
中科院分区：
文献类型：
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作者：
Fuentealba, Rodrigo A.;Liu, Qiang;Bu, Guojun
低密度脂蛋白受体相关蛋白 1 (LRP1) 是一种在神经元中大量表达的多配体受体。先前的研究表明，大脑 LRP1 水平在衰老过程中和阿尔茨海默病中会降低。尽管越来越多的证据证明LRP1在载脂蛋白E/脂蛋白和淀粉样β肽的代谢中发挥作用，但LRP1是否也在神经元存活中发挥直接作用尚不清楚。在这里，我们发现 LRP1 表达对于原代神经元在应激条件下的生存至关重要，这些应激条件包括营养撤退、细胞凋亡诱导剂的存在或淀粉样蛋白-β 诱导的神经毒性。使用慢病毒短发夹 RNA 敲低内源性 LRP1 表达，我们发现 LRP1 的缺失会导致 caspase-3 激活并增加神经元凋亡，这种效应可以通过 caspase-3 抑制剂来挽救。在 LRP1 敲低的神经元中，Akt 磷酸化减少与 caspase-3 激活之间存在相关性。值得注意的是，LRP1 敲低降低了初级神经元中胰岛素受体的水平，这表明神经元存活率下降可能是胰岛素受体信号通路受损的结果。相应地，LRP1 前脑敲除小鼠中胰岛素受体和磷酸 Akt 水平均下降。这些结果表明，LRP1通过调节胰岛素受体和Akt存活途径介导神经元的抗凋亡功能，并表明恢复阿尔茨海默病脑中LRP1的表达可能有益于抑制神经退行性变。
The low density lipoprotein receptor-related protein 1 (LRP1) is a multi-ligand receptor abundantly expressed in neurons. Previous work has shown that brain LRP1 levels are decreased during aging and in Alzheimer disease. Although mounting evidence has demonstrated a role for LRP1 in the metabolism of apolipoprotein E/lipoprotein and amyloid-beta peptide, whether LRP1 also plays a direct role in neuronal survival is not clear. Here, we show that LRP1 expression is critical for the survival of primary neurons under stress conditions including trophic withdrawal, the presence of apoptosis inducers, or amyloid-beta-induced neurotoxicity. Using lentiviral short hairpin RNA to knock down endogenous LRP1 expression, we showed that a depletion of LRP1 leads to an activation of caspase-3 and increased neuronal apoptosis, an effect that was rescued by a caspase-3 inhibitor. A correlation between decreased Akt phosphorylation and the activation of caspase-3 was demonstrated in LRP1 knocked down neurons. Notably, LRP1 knockdown decreased insulin receptor levels in primary neurons, suggesting that decreased neuronal survival might be a consequence of an impaired insulin receptor signaling pathway. Correspondingly, both insulin receptor and phospho-Akt levels were decreased in LRP1 forebrain knock-out mice. These results demonstrate that LRP1 mediates anti-apoptotic function in neurons by regulating insulin receptor and the Akt survival pathway and suggest that restoring LRP1 expression in Alzheimer disease brain might be beneficial to inhibiting neurodegeneration.