Lemur tail kinase 1 (LMTK1), previously called apoptosis-associated tyrosine kinase (AATYK), is an endosomal Ser/Thr kinase. We recently reported that LMTK1 regulates axon outgrowth, dendrite arborization and spine formation via Rab11-mediated vesicle transport. Rab11, a small GTPase regulating recycling endosome trafficking, is shown to be associated with late-onset Alzheimer’s disease (LOAD). In fact, genome-wide association studies identified many proteins regulating vesicle transport as risk factors for LOAD. Furthermore, LMTK1 has been reported to be a risk factor for frontotemporal dementia. Then, we hypothesized that LMTK1 contributes to AD development through vesicle transport and examined the effect of LMTK1 on the cellular localization of AD-related proteins, amyloid precursor protein (APP) and β-site APP cleaving enzyme 1 (BACE1). The β-cleavage of APP by BACE1 is the initial and rate-limiting step in Aβ generation. We found that LMTK1 accumulated BACE1, but not APP, to the perinuclear endosomal compartment, whereas the kinase-negative(kn) mutant of LMTK1A did not. The β-C-terminal fragment was prone to increase under overexpression of LMTK1A kn. Moreover, the expression level of LMTK1A was reduced in AD brains. These results suggest the possibility that LMTK1 is involved in AD development through the regulation of the proper endosomal localization of BACE1.

中文翻译：

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狐猴尾激酶 1 (LMTK1) 调节 β-分泌酶 BACE1 的内体定位

狐猴尾激酶 1 (LMTK1)，以前称为细胞凋亡相关酪氨酸激酶 (AATYK)，是一种内体 Ser/Thr 激酶。我们最近报道了 LMTK1 通过 Rab11 介导的囊泡转运调节轴突生长、树突树枝状化和脊柱形成。Rab11 是一种调节循环内体运输的小 GTP 酶，被证明与迟发性阿尔茨海默病 (LOAD) 相关。事实上，全基因组关联研究确定了许多调节囊泡运输的蛋白质是 LOAD 的危险因素。此外，据报道 LMTK1 是额颞叶痴呆的危险因素。然后，我们假设 LMTK1 通过囊泡转运促进 AD 发展，并检查了 LMTK1 对 AD 相关蛋白、淀粉样前体蛋白 (APP) 和 β 位点 APP 裂解酶 1 (BACE1) 细胞定位的影响。BACE1 对 APP 的 β 切割是 Aβ 生成的初始和限速步骤。我们发现 LMTK1 将 BACE1 而不是 APP 积累到核周内体区室，而 LMTK1A 的激酶阴性 (kn) 突变体没有。在 LMTK1A kn 过表达的情况下，β-C 末端片段易于增加。此外，LMTK1A 的表达水平在 AD 脑中降低。这些结果表明 LMTK1 通过调节 BACE1 的适当内体定位参与 AD 发展的可能性。此外，LMTK1A 的表达水平在 AD 脑中降低。这些结果表明 LMTK1 通过调节 BACE1 的适当内体定位参与 AD 发展的可能性。此外，LMTK1A 的表达水平在 AD 脑中降低。这些结果表明 LMTK1 通过调节 BACE1 的适当内体定位参与 AD 发展的可能性。