Center of Excellence in Neurosciences, Department of Biomedical Sciences, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, TX 79905, USA.
J Neurochem. 2013 Jan;124(1):123-32. doi: 10.1111/jnc.12051. Epub 2012 Nov 15.
Amyloid precursor protein (APP) and its secreted form, sAPP, contribute to the development of neurons in hippocampus, a brain region critical for learning and memory. Full-length APP binds the low-density lipoprotein receptor-related protein (LRP), which stimulates APP endocytosis. LRP also contributes to neurite growth. Furthermore, the receptor associated protein (RAP) binds LRP in a manner that blocks APP-LRP interactions. To elucidate APP contributions to neurite growth for full-length APP and sAPP, we cultured wild type (WT) and APP knockout (KO) neurons in sAPPα and/or RAP and measured neurite outgrowth at 1 day in vitro. Our data reveal that WT neurons had less axonal outgrowth including less axon branching. RAP treatment potentiated the inhibitory effects of APP. KO neurons had significantly more outgrowth and branching, especially in response to RAP, effects which were also associated with ERK2 activation. Our results affirm a major inhibitory role by full-length APP on all aspects of axonal and dendritic outgrowth, and show that RAP-LRP binding stimulated axon growth independently of APP. These findings support a major role for APP as an inhibitor of neurite growth and reveal novel signaling functions for LRP that may be disrupted by Alzheimer's pathology or therapies aimed at APP processing.
淀粉样前体蛋白（APP）及其分泌形式 sAPP 有助于海马体中神经元的发育，海马体是学习和记忆的关键脑区。全长 APP 与低密度脂蛋白受体相关蛋白（LRP）结合，刺激 APP 内吞作用。LRP 也有助于神经突生长。此外，受体相关蛋白（RAP）以阻断 APP-LRP 相互作用的方式与 LRP 结合。为了阐明全长 APP 和 sAPP 对神经突生长的贡献，我们在 sAPPα 和/或 RAP 中培养野生型（WT）和 APP 敲除（KO）神经元，并在体外 1 天测量神经突生长。我们的数据表明 WT 神经元的轴突生长较少，包括轴突分支较少。RAP 处理增强了 APP 的抑制作用。KO 神经元的生长和分支明显增加，特别是对 RAP 的反应，这也与 ERK2 激活有关。我们的结果证实全长 APP 对轴突和树突生长的所有方面都有主要的抑制作用，并表明 RAP-LRP 结合独立于 APP 刺激轴突生长。这些发现支持 APP 作为神经突生长抑制剂的主要作用，并揭示了 LRP 的新信号功能，这些功能可能被阿尔茨海默病病理或针对 APP 处理的治疗方法破坏。
