Fuentealba Rodrigo A, Liu Qiang, Kanekiyo Takahisa, Zhang Juan, Bu Guojun
Department of Pediatrics, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Biol Chem. 2009 Dec 4;284(49):34045-53. doi: 10.1074/jbc.M109.021030. Epub 2009 Oct 8.
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.
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，衰老过程以及阿尔茨海默病患者大脑中的LRP1水平会降低。尽管越来越多的证据表明LRP1在载脂蛋白E/脂蛋白和β淀粉样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。在此，我们表明，在包括营养剥夺、存在凋亡诱导剂或β淀粉样蛋白诱导的神经毒性等应激条件下，LRP1的表达对原代神经元的存活至关重要。使用慢病毒短发夹RNA敲低内源性LRP1表达，我们发现LRP1的缺失会导致半胱天冬酶-3的激活并增加神经元凋亡，而半胱天冬酶-3抑制剂可挽救这一效应。在敲低LRP1的神经元中证实了Akt磷酸化降低与半胱天冬酶-3激活之间的相关性。值得注意的是，敲低LRP1会降低原代神经元中的胰岛素受体水平，这表明神经元存活降低可能是胰岛素受体信号通路受损的结果。相应地，LRP1前脑敲除小鼠的胰岛素受体和磷酸化Akt水平均降低。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，并提示在阿尔茨海默病大脑中恢复LRP1表达可能有助于抑制神经退行性变。
