Wang Baiping, Yang Li, Wang Zilai, Zheng Hui
Huffington Center on Aging and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Proc Natl Acad Sci U S A. 2007 Aug 28;104(35):14140-5. doi: 10.1073/pnas.0704070104. Epub 2007 Aug 20.
The key pathological features of Alzheimer's disease include synaptic dysfunction, profound changes in the cholinergic system, and deposition of beta-amyloid peptides generated by proteolytic processing of the amyloid-beta precursor protein (APP). However, the pathways linking APP with synaptic activity and cholinergic neuronal function are poorly understood. We report here that APP is essential in regulating the presynaptic expression and activity of the high-affinity choline transporter (CHT), a molecule that mediates the rate-limiting step of cholinergic synaptic transmission in both the neuromuscular junction and central cholinergic neurons. Loss of APP leads to aberrant localization of CHT at the neuromuscular synapses and reduced CHT activity at cholinergic projections. At the cellular level, we show that APP and CHT can be found in Rab5-positive endosomal compartments and that APP affects CHT endocytosis. Furthermore, we demonstrate that APP interacts with CHT through the C-terminal domain, providing support for a specific and direct regulation of CHT by APP through protein-protein interactions. These results identify a physiological activity of APP in cholinergic neurons, and our data indicate that deregulation of APP function may contribute to cholinergic impairment and AD pathogenesis.
阿尔茨海默病的关键病理特征包括突触功能障碍、胆碱能系统的深刻变化以及由淀粉样前体蛋白（APP）的蛋白水解加工产生的β-淀粉样肽的沉积。然而，将APP与突触活动和胆碱能神经元功能联系起来的途径仍知之甚少。我们在此报告，APP在调节高亲和力胆碱转运体（CHT）的突触前表达和活性方面至关重要，CHT是一种在神经肌肉接头和中枢胆碱能神经元中介导胆碱能突触传递限速步骤的分子。APP的缺失导致CHT在神经肌肉突触处的定位异常以及胆碱能投射处CHT活性降低。在细胞水平上，我们表明APP和CHT可在Rab5阳性内体区室中发现，并且APP影响CHT的内吞作用。此外，我们证明APP通过C末端结构域与CHT相互作用，为APP通过蛋白质-蛋白质相互作用对CHT进行特异性和直接调节提供了支持。这些结果确定了APP在胆碱能神经元中的生理活性，我们的数据表明APP功能失调可能导致胆碱能损伤和AD发病机制。
