Abstract：
Aging with dysregulated metabolic and immune homeostasis stimulates pyroptosis, neuroinflammation, and cellular senescence, thus contributing to etiopathogenesis of Alzheimer\'s disease. GATA-binding protein 4 (GATA4) functions as a transcriptional factor in response to DNA damage, and is associated with neuroinflammation and cellular senescence. The role of GATA4 in Alzheimer\'s disease was investigated. GATA4 was elevated in hippocampus of Aβ1-42 fibril-infused rats. Injection with shRNA targeting GATA4 reduced escape latency with increase of time in target quadrant and number of platform crossings in Aβ1-42 fibril-infused rats. Moreover, knockdown of GATA4 ameliorated morphological changes of hippocampus and reduced amyloid plaque deposition in Aβ1-42 fibril-infused rats. Silence of GATA4 repressed neuroinflammation and apoptosis in Aβ1-42 fibril-infused rats. Loss of GATA4 in Aβ1-42 fibril-infused rats reduced the expression of specificity protein 1 (Sp1) to downregulate long noncoding RNA small nucleolar RNA host gene 1 (SNHG1) and upregulated miR-361-3p. Loss of SNHG1 ameliorated learning and memory impairments in Aβ1-42 fibril-infused rats. Overexpression of Sp1 attenuated GATA4 silence-induced decrease of escape latency, increase of time in target quadrant, and number of platform crossings in Aβ1-42 fibril-infused rats. In conclusion, silence of GATA4 ameliorated cognitive dysfunction and inhibited hippocampal inflammation and cell apoptosis through regulation of Sp1/SNHG1/miR-361-3p.
摘要：
代谢和免疫稳态失调的衰老刺激焦亡，神经炎症，和细胞衰老，从而有助于阿尔茨海默病的病因。GATA结合蛋白4（GATA4）在DNA损伤时作为转录因子发挥作用，并与神经炎症和细胞衰老有关。研究了GATA4在阿尔茨海默病中的作用。输入Aβ1-42原纤维的大鼠海马中GATA4升高。在注入Aβ1-42原纤维的大鼠中，靶向GATA4的shRNA注射减少了逃避潜伏期，增加了目标象限的时间和平台交叉的数量。此外，敲除GATA4改善了Aβ1-42原纤维输注大鼠海马的形态变化并减少了淀粉样斑块的沉积。GATA4沉默抑制Aβ1-42原纤维输注大鼠的神经炎症和细胞凋亡。输入Aβ1-42原纤维的大鼠中GATA4的丢失降低了特异性蛋白1（Sp1）的表达，以下调长非编码RNA小核仁RNA宿主基因1（SNHG1）并上调miR-361-3p。SNHG1的缺失改善了Aβ1-42原纤维输注大鼠的学习和记忆障碍。Sp1过表达减弱GATA4沉默诱导的逃逸潜伏期减少，在目标象限中增加时间，和Aβ1-42原纤维输注大鼠的平台交叉数。总之,沉默GATA4可通过调节Sp1/SNHG1/miR-361-3p改善认知功能障碍,抑制海马炎症和细胞凋亡。
