Meng Tian, Cao Qin, Lei Peng, Bush Ashley I, Xiang Qi, Su Zhijian, He Xiang, Rogers Jack T, Chiu Ing-Ming, Zhang Qihao, Huang Yadong
Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou 510632, China.
Oxidation Biology Unit, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC 3010, Australia.
Mol Ther Nucleic Acids. 2017 Jun 16;7:439-452. doi: 10.1016/j.omtn.2017.05.004. Epub 2017 May 10.
Acid fibroblast growth factor (aFGF) has shown neuroprotection in Alzheimer's disease (AD) models in previous studies, yet its mechanism is still uncertain. Here we report that the efficacy of Tat-haFGF is markedly increased when loaded cationic liposomes for intranasal delivery are intranasally administered to APP/PS1 mice. Our results demonstrated that liposomal Tat-haFGF treatment significantly ameliorated behavioral deficits, relieved brain Aβ burden, and increased the expression and activity of disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) in the brain. Tat-haFGF antagonized Aβ-induced cell death and structural damage in rat primary neurons in an ADAM10-dependent manner, which, in turn, was promoted by the activation of XBP1 splicing and modulated by the PI3K-CREB pathway. Both knockdown of ADAM10 and inhibition of PI3K (LY294002) negated Tat-haFGF rescue. Thus, Tat-haFGF activates the IRE1α/XBP1 pathway of the unfolded protein response (UPR) against the endoplasmic reticulum (ER) stress induced by Aβ, and, subsequently, the nuclear translocation of spliced XBP1 (XBP1s) promotes transcription of ADAM10. These results highlight the important role of ADAM10 and its activation through the PI3K-CREB-IRE1α/XBP1 pathway as a key factor in the mechanism of neuroprotection for Tat-haFGF.
酸性成纤维细胞生长因子（aFGF）在先前的研究中已在阿尔茨海默病（AD）模型中显示出神经保护作用，但其机制仍不确定。在此我们报告，当将负载阳离子脂质体用于鼻内递送的Tat-haFGF经鼻给予APP/PS1小鼠时，其疗效显著提高。我们的结果表明，脂质体Tat-haFGF治疗显著改善了行为缺陷，减轻了脑内Aβ负担，并增加了脑内含解整合素和金属蛋白酶结构域蛋白10（ADAM10）的表达和活性。Tat-haFGF以ADAM10依赖的方式拮抗Aβ诱导大鼠原代神经元的细胞死亡和结构损伤，而这又通过XBP1剪接的激活得到促进，并受PI3K-CREB途径调节。ADAM10的敲低和PI3K（LY294002）的抑制均否定了Tat-haFGF的挽救作用。因此，Tat-haFGF激活未折叠蛋白反应（UPR）的IRE1α/XBP1途径以对抗由Aβ诱导的内质网（ER）应激，随后，剪接的XBP1（XBP1s）的核转位促进ADAM10的转录。这些结果突出了ADAM10及其通过PI3K-CREB-IRE1α/XBP1途径激活作为Tat-haFGF神经保护机制关键因素的重要作用。
