SEPT8 modulates β-amyloidogenic processing of APP by affecting the sorting and accumulation of BACE1
SEPT8 modulates β-amyloidogenic processing of APP by affecting the sorting and accumulation of BACE1
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DOI：
10.1242/jcs.185215
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发表时间：
2016-06-01
影响因子：
4
通讯作者：
Hiltunen, Mikko
中科院分区：
文献类型：
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作者：
Kurkinen, Kaisa M. A.;Marttinen, Mikael;Hiltunen, Mikko
突触功能障碍和丧失是阿尔茨海默病的早期致病事件。有毒淀粉样β (Aβ) 肽生成的核心步骤是β 位点APP 裂解酶(BACE1) 裂解淀粉样前体蛋白(APP)。在这里，我们阐明了与突触可塑性和囊泡运输有关的 septin (SEPT) 蛋白家族成员的下调是否会影响 APP 加工和 Aβ 生成。研究发现 SEPT8 通过翻译后机制降低神经元细胞中可溶性 APPβ 和 Aβ 水平，导致 BACE1 蛋白水平降低。在人类颞叶皮层中，我们发现了特定 SEPT8 转录变体的表达变化，其方式与阿尔茨海默病相关的神经原纤维病理学相关。这些变化与β-分泌酶活性的改变有关。我们还发现，特定的阿尔茨海默病相关 SEPT8 转录变体的过度表达会增加神经元细胞中 BACE1 和 Aβ 肽的水平。这些变化与 BACE1 半衰期延长和 BACE1 在回收内体中的定位有关。这些数据表明 SEPT8 通过影响 BACE1 的细胞内分选和积累的机制来调节 APP 的 β-淀粉样蛋白生成过程。
Dysfunction and loss of synapses are early pathogenic events in Alzheimer's disease. A central step in the generation of toxic amyloid-beta (A beta) peptides is the cleavage of amyloid precursor protein (APP) by beta-site APP-cleaving enzyme (BACE1). Here, we have elucidated whether downregulation of septin (SEPT) protein family members, which are implicated in synaptic plasticity and vesicular trafficking, affects APP processing and A beta generation. SEPT8 was found to reduce soluble APP beta and A beta levels in neuronal cells through a post-translational mechanism leading to decreased levels of BACE1 protein. In the human temporal cortex, we identified alterations in the expression of specific SEPT8 transcript variants in a manner that correlated with Alzheimer's-disease-related neurofibrillary pathology. These changes were associated with altered beta-secretase activity. We also discovered that the overexpression of a specific Alzheimer's-disease-associated SEPT8 transcript variant increased the levels of BACE1 and A beta peptides in neuronal cells. These changes were related to an increased half-life of BACE1 and the localization of BACE1 in recycling endosomes. These data suggest that SEPT8 modulates beta-amyloidogenic processing of APP through a mechanism affecting the intracellular sorting and accumulation of BACE1.