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Traffic jam hypothesis: Relationship between endocytic dysfunction and Alzheimer's disease
Neurochemistry international ( IF 4.2 ) Pub Date : 2017-07-08 , DOI: 10.1016/j.neuint.2017.07.002
Nobuyuki Kimura , Katsuhiko Yanagisawa

Membrane trafficking pathways, like the endocytic pathway, carry out fundamental cellular processes that are essential for normal functioning. One such process is regulation of cell surface receptor signaling. A growing body of evidence suggests that β-amyloid protein (Aβ) plays a key role in Alzheimer's disease (AD) pathogenesis. Cleavage of Aβ from its precursor, β-amyloid precursor protein (APP), occurs through the endocytic pathway in neuronal cells. In early-stage AD, intraneuronal accumulation of abnormally enlarged endosomes is common, indicating that endosome trafficking is disrupted. Strikingly, genome-wide association studies reveal that several endocytosis-related genes are associated with AD onset. Also, recent studies demonstrate that alteration in endocytosis induces not only Aβ pathology but also the propagation of tau protein pathology, another key pathological feature of AD. Endocytic dysfunction can disrupt neuronal physiological functions, such as synaptic vesicle transport and neurotransmitter release. Thus, “traffic jams” in the endocytic pathway may be involved in AD pathogenesis and may serve as a novel target for the development of new therapeutics.



中文翻译:

交通拥堵假说:内吞功能障碍与阿尔茨海默氏病之间的关系

像内吞途径一样,膜运输途径执行基本的细胞过程,这些过程对于正常功能至关重要。一种这样的过程是细胞表面受体信号传导的调节。越来越多的证据表明,β-淀粉样蛋白(Aβ)在阿尔茨海默氏病(AD)发病机理中起关键作用。Aβ从其前体β-淀粉样蛋白前体蛋白(APP)的切割通过神经元细胞内吞途径发生。在AD的早期阶段,神经元内异常扩大的内体的蓄积是常见的,这表明内体的运输受到了干扰。引人注目的是,全基因组关联研究表明,几种与胞吞作用有关的基因与AD发作有关。还,最近的研究表明,胞吞作用的改变不仅诱导Aβ病理,而且诱导tau蛋白病理的传播,而tau蛋白病理是AD的另一个关键病理特征。内吞功能障碍可破坏神经元的生理功能,例如突触小泡转运和神经递质释放。因此,内吞途径中的“交通堵塞”可能参与了AD的发病机制,并且可以作为开发新疗法的新靶标。

更新日期:2017-07-08
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