Waldron Elaine, Heilig Catherine, Schweitzer Andrea, Nadella Nirupa, Jaeger Sebastian, Martin Anne M, Weggen Sascha, Brix Klaudia, Pietrzik Claus U
Institute of Physiological Chemistry and Pathobiochemistry, Molecular Neurodegeneration, Johannes Gutenberg-University Mainz, 55099 Mainz, Germany.
Neurobiol Dis. 2008 Aug;31(2):188-97. doi: 10.1016/j.nbd.2008.04.006. Epub 2008 May 3.
The amyloid beta peptide (A beta) is a central player in Alzheimer's disease (AD) pathology. A beta liberation depends on APP cleavage by beta- and gamma-secretases. The low density lipoprotein receptor related protein 1 (LRP1) was shown to mediate APP processing at multiple steps. Newly synthesized LRP1 can interact with APP, implying an interaction between these two proteins early in the secretory pathway. We wanted to investigate whether LRP1 mediates APP trafficking along the secretory pathway, and, if so, whether it affects APP processing. Indeed, the early trafficking of APP within the secretory pathway is strongly influenced by its interaction with the C-terminal domain of LRP1. The LRP1-construct expressing an ER-retention motif, LRP-CT KKAA, had the capacity to retard APP traffic to early secretory compartments. In addition, we provide evidence that APP metabolism occurs in close conjunction with LRP1 trafficking, highlighting a new role of lipoprotein receptors in neurodegenerative diseases.
淀粉样β肽（Aβ）是阿尔茨海默病（AD）病理过程中的核心因素。Aβ的释放依赖于β和γ分泌酶对淀粉样前体蛋白（APP）的切割。低密度脂蛋白受体相关蛋白1（LRP1）已被证明在多个步骤中介导APP的加工过程。新合成的LRP1可与APP相互作用，这意味着这两种蛋白质在分泌途径的早期存在相互作用。我们想研究LRP1是否介导APP在分泌途径中的运输，如果是，它是否会影响APP的加工过程。事实上，APP在分泌途径中的早期运输受到其与LRP1 C末端结构域相互作用的强烈影响。表达内质网滞留基序LRP-CT KKAA的LRP1构建体有能力延缓APP向早期分泌小室的运输。此外，我们提供的证据表明，APP代谢与LRP1运输密切相关，这突出了脂蛋白受体在神经退行性疾病中的新作用。
