Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093, USA.
Hum Mol Genet. 2012 Nov 1;21(21):4587-601. doi: 10.1093/hmg/dds297. Epub 2012 Jul 27.
Alzheimer's disease (AD) is a neurodegenerative disease pathologically characterized by amyloid plaques and neurofibrillary tangles in the brain. Before these hallmark features appear, signs of axonal transport defects develop, though the initiating events are not clear. Enhanced amyloidogenic processing of amyloid precursor protein (APP) plays an integral role in AD pathogenesis, and previous work suggests that both the Aβ region and the C-terminal fragments (CTFs) of APP can cause transport defects. However, it remains unknown if APP processing affects the axonal transport of APP itself, and whether increased APP processing is sufficient to promote axonal dystrophy. We tested the hypothesis that β-secretase cleavage site mutations of APP alter APP axonal transport directly. We found that the enhanced β-secretase cleavage reduces the anterograde axonal transport of APP, while inhibited β-cleavage stimulates APP anterograde axonal transport. Transport behavior of APP after treatment with β- or γ-secretase inhibitors suggests that the amount of β-secretase cleaved CTFs (βCTFs) of APP underlies these transport differences. Consistent with these findings, βCTFs have reduced anterograde axonal transport compared with full-length, wild-type APP. Finally, a gene-targeted mouse with familial AD (FAD) Swedish mutations to APP, which enhance the β-cleavage of APP, develops axonal dystrophy in the absence of mutant protein overexpression, amyloid plaque deposition and synaptic degradation. These results suggest that the enhanced β-secretase processing of APP can directly impair the anterograde axonal transport of APP and are sufficient to lead to axonal defects in vivo.
阿尔茨海默病（AD）是一种神经退行性疾病，其病理学特征为大脑中的淀粉样斑块和神经原纤维缠结。在出现这些标志性特征之前，轴突运输缺陷的迹象就已经出现，尽管起始事件尚不清楚。淀粉样前体蛋白（APP）的增强型淀粉样蛋白生成处理在 AD 的发病机制中起着重要作用，先前的工作表明，Aβ 区域和 APP 的 C 末端片段（CTFs）都可能导致运输缺陷。然而，目前尚不清楚 APP 处理是否会影响 APP 本身的轴突运输，以及增加的 APP 处理是否足以促进轴突萎缩。我们检验了这样一个假设，即 APP 的β-分泌酶切割位点突变会直接改变 APP 的轴突运输。我们发现增强的β-分泌酶切割会降低 APP 的顺行性轴突运输，而抑制β-切割会刺激 APP 的顺行性轴突运输。用β-或γ-分泌酶抑制剂处理 APP 后的运输行为表明，APP 的β-分泌酶切割 CTFs（βCTFs）的数量是这些运输差异的基础。这些发现与βCTFs 与全长野生型 APP 相比，其顺行性轴突运输减少的结果一致。最后，一种携带有家族性 AD（FAD）瑞典突变的 APP 的基因靶向小鼠，增强了 APP 的β-切割，在没有突变蛋白过表达、淀粉样斑块沉积和突触降解的情况下，就会出现轴突萎缩。这些结果表明，APP 的增强型β-分泌酶处理可以直接损害 APP 的顺行性轴突运输，并足以导致体内的轴突缺陷。
