Inhibition of death-associated protein kinase 1 attenuates the phosphorylation and amyloidogenic processing of amyloid precursor protein
Inhibition of death-associated protein kinase 1 attenuates the phosphorylation and amyloidogenic processing of amyloid precursor protein
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DOI：
10.1093/hmg/ddw114
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发表时间：
2016-06-15
影响因子：
3.5
通讯作者：
Lee, Tae Ho
中科院分区：
文献类型：
--
作者：
Kim, Byeong Mo;You, Mi-Hyeon;Lee, Tae Ho
淀粉样前体蛋白（APP）连续裂解后的代谢产物--β淀粉样蛋白（A β）肽在细胞外的沉积是阿尔茨海默病（AD）发病机制中的关键步骤。虽然死亡相关蛋白激酶1（DAPK 1）在AD大脑中高度表达，其遗传变异与AD风险有关，但关于DAPK 1对APP代谢和A β生成的影响知之甚少。在这项研究中，我们使用细胞培养和小鼠模型证明了DAPK 1在APP加工调节中的新作用。在神经元细胞培养模型中，DAPK 1（而不是其激酶缺陷突变体（K42 A））显著增加了人A β分泌。此外，敲低DAPK 1表达或抑制DAPK 1催化活性显著降低A β分泌。此外，DAPK 1而不是K42 A触发了APP的Thr 668磷酸化，这可能启动并促进淀粉样蛋白生成APP加工，导致A β的产生。在Tg 2576 APPsw过表达小鼠中，DAPK 1敲除使APP加工向非淀粉样蛋白生成途径转移，并减少A β生成。最后，在AD脑中，升高的DAPK 1水平与APP磷酸化的增加相关。结合在一起，这些结果表明，DAPK 1促进APP的磷酸化和淀粉样蛋白的加工，这可能是AD的潜在治疗靶点。
Extracellular deposition of amyloid-beta (A beta) peptide, a metabolite of sequential cleavage of amyloid precursor protein (APP), is a critical step in the pathogenesis of Alzheimer's disease (AD). While death-associated protein kinase 1 (DAPK1) is highly expressed in AD brains and its genetic variants are linked to AD risk, little is known about the impact of DAPK1 on APP metabolism and A beta generation. In this study, we demonstrated a novel effect of DAPK1 in the regulation of APP processing using cell culture and mouse models. DAPK1, but not its kinase deficient mutant (K42A), significantly increased human A beta secretion in neuronal cell culture models. Moreover, knockdown of DAPK1 expression or inhibition of DAPK1 catalytic activity significantly decreased A beta secretion. Furthermore, DAPK1, but not K42A, triggered Thr668 phosphorylation of APP, which may initiate and facilitate amyloidogenic APP processing leading to the generation of A beta. In Tg2576 APPswe-overexpressing mice, knockout of DAPK1 shifted APP processing toward non-amyloidogenic pathway and decreased A beta generation. Finally, in AD brains, elevated DAPK1 levels showed co-relation with the increase of APP phosphorylation. Combined together, these results suggest that DAPK1 promotes the phosphorylation and amyloidogenic processing of APP, and that may serve a potential therapeutic target for AD.