星形胶质细胞ZHX2调控Notch通路在Aβ寡聚体诱导线粒体功能紊乱与记忆损伤中的作用及机制研究

线粒体功能紊乱是阿尔茨海默症（AD）患者的病理特征，改善线粒体代谢被视为治疗AD的潜在策略。可溶性Aβ寡聚体（oAβ）作为AD脑内主要神经毒性物质，可引起星形胶质细胞线粒体功能异常和记忆损伤，但机制尚不明确。转录因子ZHX2在脑内广泛表达。我们前期研究发现ZHX2高表达于星形胶质细胞中并在AD患者海马脑区显著升高。敲除星形胶质细胞ZHX2加重oAβ导致的小鼠记忆损伤并抑制线粒体ATP合成相关基因表达。过表达ZHX2缓解oAβ引起的ATP合成受损。Notch1作为ZHX2转录抑制靶点，可能是ZHX2调控星形胶质细胞线粒体代谢的重要途径。我们拟采用ZHX2转基因与AD小鼠、RNA测序、线粒体荧光探针、细胞代谢检测分析星形胶质细胞ZHX2在oAβ诱导记忆损伤与线粒体功能紊乱中的作用，并阐明ZHX2在其中的作用机制。本研究有望揭示星形胶质细胞线粒体代谢损伤机制，为AD疾病的临床治疗提供理论依据。

Mitochondrial dysfunction is a common feature of Alzheimer’s disease (AD). Novel research effort aimed at boosting mitochondrial and bioenergetic function is regarded as an alternative treatment strategy. Soluble Aβ oligomers (oAβ) is one of the most neurotoxic form in AD. The accumulation of oAβ has been suggested to trigger astrocytic mitochondrial dysfunction and memory loss. However, the mechanism is still not fully understood. Zinc-fingers and homeoboxes 2 (ZHX2), an important transcription factor, is highly expressed in brain. Immunofluorescent staining showed that ZHX2 is mainly expressed in astrocytes. According to GEO data, we found that ZHX2 was increased in the hippocampus of AD patients. Conditional knock down of ZHX2 in astrocytes significantly exacerbated oAβ-induced memory deficits and reduced the expression of mitochondrial ATP synthesis-related genes. Overexpression of ZHX2 rescued oAβ-decreased ATP production in primary astrocytes. Notch1, a target gene of ZHX2, may participate in ZHX2-regulated astrocytic mitochondrial metabolism. On the basis of the previous study, we will further investigate the effect and mechanism of astrocyte ZHX2 in oAβ-induced memory loss and mitochondrial dysfunction by using ZHX2 transgenic and APP/PS1 mice, RNA-Seq, ECAR and OCR experiments, and mitochondrial fluorescent probe, which will provide novel insights into the pathogenesis and therapeutic strategy of AD diseases.