Department of Human Biology and Human Genetics, University of Kaiserslautern, 67663, Kaiserslautern, Germany.
Institute for Molecular and Cellular Cognition, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany.
Mol Neurobiol. 2018 Jul;55(7):5809-5829. doi: 10.1007/s12035-017-0806-x. Epub 2017 Oct 27.
The amyloid precursor protein (APP), one key player in Alzheimer's disease (AD), is extensively processed by different proteases. This leads to the generation of diverging fragments including the amyloid β (Aβ) peptide, which accumulates in brains of AD patients. Subcellular trafficking of APP is an important aspect for its proteolytic conversion, since the various secretases which cleave APP are located in different cellular compartments. As a consequence, altered subcellular targeting of APP is thought to directly affect the degree to which Aβ is generated. The mechanisms underlying intracellular APP transport are critical to understand AD pathogenesis and can serve as a target for future pharmacological interventions. In the recent years, a number of APP interacting proteins were identified which are implicated in sorting of APP, thereby influencing APP processing at different angles of the secretory or endocytic pathway. This review provides an update on the proteolytic processing of APP and the interplay of the transmembrane proteins low-density lipoprotein receptor-related protein 1, sortilin-receptor with A-type repeats, SorCS1c, sortilin, and calsyntenin. We discuss the specific interactions with APP, the capacity to modulate the intracellular itinerary and the proteolytic conversion of APP, a possible involvement in the clearance of Aβ, and the implications of these transmembrane proteins in AD and other neurodegenerative diseases.
淀粉样前体蛋白（APP）是阿尔茨海默病（AD）的关键蛋白之一，它被多种蛋白酶广泛加工。这导致生成了不同的片段，包括淀粉样β（Aβ）肽，它在 AD 患者的大脑中积累。APP 的细胞内运输是其蛋白水解转化的一个重要方面，因为切割 APP 的各种分泌酶位于不同的细胞区室中。因此，APP 的亚细胞靶向改变被认为直接影响 Aβ的生成程度。了解 AD 发病机制的关键是理解细胞内 APP 转运的机制，并可以作为未来药物干预的靶点。近年来，已经鉴定出许多与 APP 相互作用的蛋白质，这些蛋白质参与 APP 的分拣，从而从不同角度影响 APP 在分泌或内吞途径中的加工。这篇综述介绍了 APP 的蛋白水解加工以及跨膜蛋白低密度脂蛋白受体相关蛋白 1、A 型重复的分选素受体、 SorCS1c、分选素和钙黏蛋白之间的相互作用。我们讨论了与 APP 的特定相互作用、调节细胞内途径和 APP 的蛋白水解转化的能力、在 Aβ清除中的可能参与以及这些跨膜蛋白在 AD 和其他神经退行性疾病中的意义。
