Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, Oregon 97239, USA.
J Neurosci. 2012 Nov 14;32(46):16181-92. doi: 10.1523/JNEUROSCI.0228-12.2012.
β-secretase (or BACE1) is the key enzyme in the production of β-amyloid (Aβ), which accumulates in the senile plaques characteristic for Alzheimer's disease. Consequently, the lack of BACE1 prevents β-processing of the amyloid precursor protein and Aβ production, which made it a promising target for drug development. However, the loss of BACE1 is also detrimental, leading to myelination defects and altered neuronal activity, functions that have been associated with the cleavage of Neuregulin and a voltage-gated sodium channel subunit. Here we show that the Drosophila ortholog of BACE, dBACE, is required for glial survival. Cell-specific knockdown experiments reveal that this is a non-cell autonomous function, as a knockdown of dBACE in photoreceptor neurons leads to progressive degeneration of glia in their target zone, the lamina. Interestingly, this phenotype is suppressed by the loss of the fly amyloid precursor protein (APPL), whereas a secretion-deficient form of APPL enhances the degeneration. This shows that full-length APPL in neurons promotes the death of neighboring glial cells and that β-processing of APPL is needed to prevent glial death. These results therefore not only demonstrate a novel function for an APP protein in glia, but they also show this function specifically requires regulation by β-cleavage.
β-分泌酶（或 BACE1）是β-淀粉样蛋白（Aβ）产生的关键酶，Aβ 在阿尔茨海默病特征性的老年斑中积累。因此，缺乏 BACE1 可防止淀粉样前体蛋白的β-加工和 Aβ 的产生，这使其成为药物开发的有希望的靶点。然而，BACE1 的缺失也是有害的，导致髓鞘形成缺陷和神经元活动改变，这些功能与神经调节素和电压门控钠离子通道亚基的切割有关。在这里，我们表明 BACE 的果蝇同源物 dBACE 对于神经胶质细胞的存活是必需的。细胞特异性敲低实验表明，这是一种非细胞自主的功能，因为在光感受器神经元中敲低 dBACE 会导致其靶区（lamina）中的神经胶质细胞逐渐退化。有趣的是，这种表型可以被果蝇淀粉样前体蛋白（APPL）的缺失所抑制，而 APPL 的分泌缺陷形式则增强了退化。这表明神经元中的全长 APPL 促进了邻近神经胶质细胞的死亡，并且需要 APPL 的β-加工来防止神经胶质细胞死亡。因此，这些结果不仅证明了 APP 蛋白在神经胶质细胞中的一个新功能，而且还表明这种功能特别需要β-切割的调节。
