β-secretase cleavage of the fly amyloid precursor protein is required for glial survival.
β-secretase cleavage of the fly amyloid precursor protein is required for glial survival.
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DOI：
10.1523/jneurosci.0228-12.2012
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发表时间：
2012-11-14
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影响因子：
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通讯作者：
Kretzschmar D
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文献类型：
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作者：
Bolkan BJ;Triphan T;Kretzschmar D
β-分泌酶（β-secretase，BACE1）是产生β-淀粉样蛋白（β-amyloid，A β）的关键酶，A β在阿尔茨海默病（Alzheimer's Disease，AD）的老年斑中积累。因此，BACE1的缺乏阻止了淀粉样前体蛋白（APP）的β加工和A β的产生，这使其成为药物开发的一个有前途的靶点。然而，BACE1的丢失也是有害的，导致髓鞘形成缺陷和神经元活性改变，这些功能与神经调节蛋白和电压门控钠通道亚基的裂解相关。在这里，我们表明，果蝇直系同源的BACE，dBACE，是胶质细胞的生存所必需的。细胞特异性敲低实验表明，这是一种非细胞自主功能，因为在感光神经元中dBACE的敲低导致其靶区（椎板）中神经胶质细胞的进行性变性。有趣的是，这种表型被果蝇淀粉样前体蛋白（APPL）的丢失所抑制，而APPL的分泌缺陷形式增强了变性。这表明神经元中的全长APPL促进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蛋白在神经胶质中的新功能，而且还表明这种功能特别需要β-切割的调节。
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 (AD). Consequently, the lack of BACE1 prevents β-processing of the Amyloid Precursor Protein (APP) 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 orthologue 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.