Yan Xu, Nykänen Niko-Petteri, Brunello Cecilia A, Haapasalo Annakaisa, Hiltunen Mikko, Uronen Riikka-Liisa, Huttunen Henri J
Neuroscience Center, University of Helsinki, FI-00014 Helsinki, Finland.
Institute of Clinical Medicine-Neurology, University of Eastern Finland, FI-70211 Kuopio, Finland Department of Neurology, Kuopio University Hospital, FI-70029 Kuopio, Finland Institute of Biomedicine, University of Eastern Finland, FI-70211 Kuopio, Finland.
J Cell Sci. 2016 May 15;129(10):2003-15. doi: 10.1242/jcs.180745. Epub 2016 Apr 4.
One of the defining pathological features of Alzheimer's disease is the intraneuronal accumulation of tau (also known as MAPT) protein. Tau is also secreted from neurons in response to various stimuli and accumulates in the cerebrospinal fluid of Alzheimer's disease patients. Tau pathology might spread from cell to cell through a mechanism involving secretion and uptake. Here, we developed an assay to follow cellular release and uptake of tau dimers. Individual silencing of ten common late-onset Alzheimer's disease risk genes in HEK293T cells expressing the tau reporters suggested that FRMD4A is functionally linked to tau secretion. FRMD4A depletion by using RNA interference (RNAi) reduced and overexpression increased tau secretion. The activity of cytohesins, interactors of FRMD4A and guanine-nucleotide-exchange factors of Arf6, was necessary for FRMD4A-induced tau secretion. Increased Arf6 and cell polarity signaling through Par6 and atypical protein kinase Cζ (aPKCζ) stimulated tau secretion. In mature cortical neurons, FRMD4A RNAi or inhibition of cytohesins strongly upregulated secretion of endogenous tau. These results suggest that FRMD4A, a genetic risk factor for late-onset Alzheimer's disease, regulates tau secretion by activating cytohesin-Arf6 signaling. We conclude that genetic risk factors of Alzheimer's disease might modulate disease progression by altering tau secretion.
阿尔茨海默病的一个典型病理特征是神经元内tau（也称为MAPT）蛋白的积累。tau蛋白也会在各种刺激下从神经元分泌出来，并在阿尔茨海默病患者的脑脊液中积累。tau病理可能通过一种涉及分泌和摄取的机制在细胞间传播。在这里，我们开发了一种检测方法来跟踪tau二聚体的细胞释放和摄取。在表达tau报告基因的HEK293T细胞中，对十个常见的晚发性阿尔茨海默病风险基因进行单独沉默，结果表明FRMD4A在功能上与tau分泌有关。使用RNA干扰（RNAi）耗尽FRMD4A会减少tau分泌，而过表达则会增加tau分泌。细胞鸟苷酸交换因子cytohesins作为FRMD4A的相互作用蛋白以及Arf6的鸟苷酸交换因子，其活性对于FRMD4A诱导的tau分泌是必需的。通过Par6和非典型蛋白激酶Cζ（aPKCζ）增加Arf6和细胞极性信号会刺激tau分泌。在成熟的皮质神经元中，FRMD4A RNAi或细胞鸟苷酸交换因子的抑制会强烈上调内源性tau的分泌。这些结果表明，晚发性阿尔茨海默病的遗传风险因子FRMD4A通过激活细胞鸟苷酸交换因子-Arf6信号来调节tau分泌。我们得出结论，阿尔茨海默病的遗传风险因子可能通过改变tau分泌来调节疾病进展。
