Stokin Gorazd B, Almenar-Queralt Angels, Gunawardena Shermali, Rodrigues Elizabeth M, Falzone Tomás, Kim Jungsu, Lillo Concepción, Mount Stephanie L, Roberts Elizabeth A, McGowan Eileen, Williams David S, Goldstein Lawrence S B
Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0683, USA.
Hum Mol Genet. 2008 Nov 15;17(22):3474-86. doi: 10.1093/hmg/ddn240. Epub 2008 Aug 11.
Overexpression of amyloid precursor protein (APP), as well as mutations in the APP and presenilin genes, causes rare forms of Alzheimer's disease (AD). These genetic changes have been proposed to cause AD by elevating levels of amyloid-beta peptides (Abeta), which are thought to be neurotoxic. Since overexpression of APP also causes defects in axonal transport, we tested whether defects in axonal transport were the result of Abeta poisoning of the axonal transport machinery. Because directly varying APP levels also alters APP domains in addition to Abeta, we perturbed Abeta generation selectively by combining APP transgenes in Drosophila and mice with presenilin-1 (PS1) transgenes harboring mutations that cause familial AD (FAD). We found that combining FAD mutant PS1 with FAD mutant APP increased Abeta42/Abeta40 ratios and enhanced amyloid deposition as previously reported. Surprisingly, however, this combination suppressed rather than increased APP-induced axonal transport defects in both Drosophila and mice. In addition, neuronal apoptosis induced by expression of FAD mutant human APP in Drosophila was suppressed by co-expressing FAD mutant PS1. We also observed that directly elevating Abeta with fusions to the Familial British and Danish Dementia-related BRI protein did not enhance axonal transport phenotypes in APP transgenic mice. Finally, we observed that perturbing Abeta ratios in the mouse by combining FAD mutant PS1 with FAD mutant APP did not enhance APP-induced behavioral defects. A potential mechanism to explain these findings was suggested by direct analysis of axonal transport in the mouse, which revealed that axonal transport or entry of APP into axons is reduced by FAD mutant PS1. Thus, we suggest that APP-induced axonal defects are not caused by Abeta.
淀粉样前体蛋白（APP）的过表达以及APP和早老素基因的突变会导致罕见形式的阿尔茨海默病（AD）。这些基因变化被认为是通过提高淀粉样β肽（Aβ）的水平来引发AD的，而Aβ被认为具有神经毒性。由于APP的过表达也会导致轴突运输缺陷，我们测试了轴突运输缺陷是否是轴突运输机制被Aβ毒害的结果。因为直接改变APP水平除了会改变Aβ外还会改变APP结构域，所以我们通过将果蝇和小鼠中的APP转基因与携带导致家族性AD（FAD）的突变的早老素-1（PS1）转基因相结合，选择性地干扰Aβ的产生。我们发现，将FAD突变型PS1与FAD突变型APP相结合会增加Aβ42/Aβ40的比例，并增强淀粉样蛋白沉积，正如之前所报道的那样。然而，令人惊讶的是，这种组合在果蝇和小鼠中都抑制而非增加了APP诱导的轴突运输缺陷。此外，在果蝇中共同表达FAD突变型PS1可抑制由FAD突变型人APP表达诱导的神经元凋亡。我们还观察到，将与家族性英国和丹麦痴呆相关的BRI蛋白融合以直接提高Aβ水平，并不会增强APP转基因小鼠的轴突运输表型。最后，我们观察到，通过将FAD突变型PS1与FAD突变型APP相结合来干扰小鼠体内的Aβ比例，并不会增强APP诱导的行为缺陷。对小鼠轴突运输的直接分析提示了一种解释这些发现的潜在机制，该分析表明FAD突变型PS1会减少轴突运输或APP进入轴突的过程。因此，我们认为APP诱导的轴突缺陷不是由Aβ引起的。
