Kins Stefan, Lauther Nadine, Szodorai Anita, Beyreuther Konrad
Zentrum für Molekulare Biologie der Universität Heidelberg, Heidelberg, Germany.
Neurodegener Dis. 2006;3(4-5):218-26. doi: 10.1159/000095259.
Changes in the intracellular transport of amyloid precursor protein (APP) affect the extent to which APP is exposed to alpha- or beta-secretase in a common subcellular compartment and therefore directly influence the degree to which APP undergoes the amyloidogenic pathway leading to generation of beta-amyloid. As the presynaptic regions of neurons are thought to be the main source of beta-amyloid in the brain, attention has been focused on axonal APP trafficking. APP is transported along axons by a fast, kinesin-dependent anterograde transport mechanism. Despite the wealth of in vivo and in vitro data that have accumulated regarding the connection of APP to kinesin transport, it is not yet clear if APP is coupled to its specific motor protein via an intracellular interaction partner, such as the c-Jun N-terminal kinase-interacting protein, or by yet another unknown molecular mechanism. The cargo proteins that form a functional complex with APP are also unknown. Due to the long lifespan, and vast extent, of neurons, in particular axons, neurons are highly sensitive to changes in subcellular transport. Recent in vitro and in vivo studies have shown that variations in APP or tau affect mitochondrial and synaptic vesicle transport. Further, it was shown that this axonal dysfunction might lead to impaired synaptic plasticity, which is crucial for neuronal viability and function. Thus, changes in APP and tau expression may cause perturbed axonal transport and changes in APP processing, contributing to cognitive decline and neurodegeneration in Alzheimer's disease.
淀粉样前体蛋白（APP）细胞内运输的变化会影响APP在一个共同亚细胞区室中与α-或β-分泌酶接触的程度，因此直接影响APP进入导致β-淀粉样蛋白生成的淀粉样生成途径的程度。由于神经元的突触前区域被认为是大脑中β-淀粉样蛋白的主要来源，因此注意力集中在轴突APP运输上。APP通过一种快速的、依赖驱动蛋白的顺行运输机制沿轴突运输。尽管已经积累了大量关于APP与驱动蛋白运输联系的体内和体外数据，但尚不清楚APP是通过细胞内相互作用伙伴（如c-Jun N端激酶相互作用蛋白）还是通过另一种未知分子机制与特定的运动蛋白偶联。与APP形成功能复合物的货物蛋白也未知。由于神经元，特别是轴突的寿命长且范围广，神经元对亚细胞运输的变化高度敏感。最近的体外和体内研究表明，APP或tau的变化会影响线粒体和突触小泡运输。此外，研究表明这种轴突功能障碍可能导致突触可塑性受损，而突触可塑性对神经元的生存能力和功能至关重要。因此，APP和tau表达的变化可能导致轴突运输紊乱和APP加工变化，从而导致阿尔茨海默病的认知衰退和神经退行性变。
