Kurkinen Kaisa M A, Marttinen Mikael, Turner Laura, Natunen Teemu, Mäkinen Petra, Haapalinna Fanni, Sarajärvi Timo, Gabbouj Sami, Kurki Mitja, Paananen Jussi, Koivisto Anne M, Rauramaa Tuomas, Leinonen Ville, Tanila Heikki, Soininen Hilkka, Lucas Fiona R, Haapasalo Annakaisa, Hiltunen Mikko
Institute of Biomedicine, School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland.
Eisai Ltd., Bernard Katz Building, University College London, London WC1E 6BT, UK.
J Cell Sci. 2016 Jun 1;129(11):2224-38. doi: 10.1242/jcs.185215. Epub 2016 Apr 15.
Dysfunction and loss of synapses are early pathogenic events in Alzheimer's disease. A central step in the generation of toxic amyloid-β (Aβ) peptides is the cleavage of amyloid precursor protein (APP) by β-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 Aβ generation. SEPT8 was found to reduce soluble APPβ and Aβ 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 β-secretase activity. We also discovered that the overexpression of a specific Alzheimer's-disease-associated SEPT8 transcript variant increased the levels of BACE1 and Aβ 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 β-amyloidogenic processing of APP through a mechanism affecting the intracellular sorting and accumulation of BACE1.
突触功能障碍和丧失是阿尔茨海默病早期的致病事件。有毒淀粉样β（Aβ）肽生成的一个关键步骤是淀粉样前体蛋白（APP）被β位点APP切割酶（BACE1）切割。在此，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通过一种导致BACE1蛋白水平降低的翻译后机制，降低神经元细胞中可溶性APPβ和Aβ水平。在人类颞叶皮质中，我们发现特定SEPT8转录变体的表达变化与阿尔茨海默病相关的神经原纤维病理变化相关。这些变化与β分泌酶活性改变有关。我们还发现，一种与阿尔茨海默病相关的特定SEPT8转录变体的过表达增加了神经元细胞中BACE1和Aβ肽的水平。这些变化与BACE1半衰期延长以及BACE1在循环内体中的定位有关。这些数据表明，SEPT8通过影响BACE1细胞内分选和积累的机制调节APP的β淀粉样生成加工。
