Harris-White M E, Frautschy S A
University of California, Los Angeles, Department of Medicine, and the Veterans Administration Greater Los Angeles Healthcare System, Sepulveda 91343, USA.
Curr Drug Targets CNS Neurol Disord. 2005 Oct;4(5):469-80. doi: 10.2174/156800705774322102.
This review will focus primarily on the role of the low density lipoprotein receptor-related protein (LRP-1) in neuronal synapse formation and function in Alzheimer's Disease (AD). We review the role that its ligands may have in cognition or AD: apolipoprotein E (ApoE), alpha2-macroglobulin, Transforming Growth Factor-Beta (TGFbeta, Tissue Plasminogen Activator (tPA), insulin growth factor binding protein-3 (IGFBP-3), which all bind LRP-1 and apolipoprotein J (ApoJ), which is a ligand for LRP-2. After reviewing its role as a signaling receptor, we discuss the connection between LRP and the NMDA glutamate receptor via the post synaptic density 95 (PSD-95) neuronal scaffold protein and the implications it may have for memory and cognition. Finally, we discuss the evidence supporting a role for LRP in AD. Although the evidence for LRP as a genetic risk factor is weak, many of its ligands impose genetic risk, and have been implicated in AD pathogenic cascades. We discuss the role of LRP in amyloid precursor protein (APP) processing and production of beta-amyloid (Abeta. We identify LRP ligands that accelerate aggregation of toxic Abeta species. LRP mediates crucial pathways in AD pathogenesis such as Abeta clearance, Abeta uptake, intraneuronal Abeta accumulation and Abeta-associated neuron death. Interestingly, the TGFbeta -V receptor is LRP-1. Data show that one critical ligand TGFbeta2, associated with neurodegeneration in amyloid diseases, induces LRP expression in PC12 cells. Data from rodent infusion models demonstrate the impact of TGFbeta2 in modifying Abeta- induced Long Term Potentiation (LTP) responses, presynaptic proteins, lipid peroxidation, gliosis and staining for neuronal nuclei. The evidence supports a complex and significant role of LRP in cognition and AD.
本综述将主要聚焦低密度脂蛋白受体相关蛋白（LRP - 1）在阿尔茨海默病（AD）中神经元突触形成及功能方面的作用。我们回顾其配体在认知或AD中可能发挥的作用：载脂蛋白E（ApoE）、α2 - 巨球蛋白、转化生长因子 - β（TGFβ）、组织纤溶酶原激活物（tPA）、胰岛素样生长因子结合蛋白 - 3（IGFBP - 3），它们均与LRP - 1结合，以及载脂蛋白J（ApoJ），其为LRP - 2的配体。在回顾其作为信号受体的作用后，我们讨论LRP与N - 甲基 - D - 天冬氨酸（NMDA）谷氨酸受体通过突触后致密蛋白95（PSD - 95）神经元支架蛋白建立的联系及其对记忆和认知可能产生的影响。最后，我们讨论支持LRP在AD中发挥作用的证据。尽管LRP作为遗传风险因素的证据薄弱，但其许多配体具有遗传风险，并已涉及AD致病级联反应。我们讨论LRP在淀粉样前体蛋白（APP）加工及β - 淀粉样蛋白（Aβ）产生中的作用。我们确定可加速有毒Aβ物种聚集的LRP配体。LRP介导AD发病机制中的关键途径，如Aβ清除、Aβ摄取、神经元内Aβ积累及Aβ相关的神经元死亡。有趣的是，TGFβ - V受体是LRP - 1。数据表明，与淀粉样疾病神经退行性变相关的一种关键配体TGFβ2可诱导PC12细胞中LRP表达。来自啮齿动物输注模型的数据证明了TGFβ2在改变Aβ诱导的长时程增强（LTP）反应、突触前蛋白、脂质过氧化、神经胶质增生及神经元细胞核染色方面的影响。证据支持LRP在认知和AD中具有复杂且重要的作用。
