Hum Mol Genet. 2013 Oct 1;22(19):3828-43. doi: 10.1093/hmg/ddt237. Epub 2013 May 24.
Neurons and other cells require intracellular transport of essential components for viability and function. Previous work has shown that while net amyloid precursor protein (APP) transport is generally anterograde, individual vesicles containing APP move bi-directionally. This discrepancy highlights our poor understanding of the in vivo regulation of APP-vesicle transport. Here, we show that reduction of presenilin (PS) or suppression of gamma-secretase activity substantially increases anterograde and retrograde velocities for APP vesicles. Strikingly, PS deficiency has no effect on an unrelated cargo vesicle class containing synaptotagmin, which is powered by a different kinesin motor. Increased velocities caused by PS or gamma-secretase reduction require functional kinesin-1 and dynein motors. Together, our findings suggest that a normal function of PS is to repress kinesin-1 and dynein motor activity during axonal transport of APP vesicles. Furthermore, our data suggest that axonal transport defects induced by loss of PS-mediated regulatory effects on APP-vesicle motility could be a major cause of neuronal and synaptic defects observed in Alzheimer's Disease (AD) pathogenesis. Thus, perturbations of APP/PS transport could contribute to early neuropathology observed in AD, and highlight a potential novel therapeutic pathway for early intervention, prior to neuronal loss and clinical manifestation of disease.
神经元和其他细胞需要将基本成分在细胞内运输，以维持其存活和功能。先前的研究表明，尽管 APP（淀粉样前体蛋白）的净运输通常是顺行的，但含有 APP 的囊泡却可以双向移动。这种差异突出表明我们对 APP-囊泡运输的体内调节知之甚少。在这里，我们发现降低早老素（PS）或抑制γ-分泌酶活性会显著增加 APP 囊泡的顺行和逆行速度。引人注目的是，PS 缺乏对含有突触融合蛋白的另一种无关货物囊泡类没有影响，而该囊泡类由不同的驱动蛋白提供动力。PS 或 γ-分泌酶减少引起的速度增加需要功能性驱动蛋白-1 和动力蛋白。总之，我们的研究结果表明，PS 的正常功能是在 APP 囊泡的轴突运输过程中抑制驱动蛋白-1 和动力蛋白的活性。此外，我们的数据表明，由于 PS 对 APP-囊泡运动的调节作用丧失而导致的轴突运输缺陷可能是阿尔茨海默病（AD）发病机制中观察到的神经元和突触缺陷的主要原因。因此，APP/PS 运输的扰动可能导致 AD 中观察到的早期神经病理学，并强调了在神经元丧失和疾病临床表现之前进行早期干预的潜在新治疗途径。
