Abstract：
Vascular dementia (VD), a progressive vascular cognitive impairment, is characterised by the presence of cerebral hypoperfusion, increased blood-brain barrier permeability, and white matter lesions. Although current treatment strategies primarily focus on risk factors such as hypertension, diabetes, and heart disease, efficient and targeted therapies are lacking and the underlying mechanisms of VD remain unclear. We previously discovered that Apelin receptors (APJ), which are G protein-coupled receptors (GPCRs), can homodimerize and generate signals that are distinct from those of APJ monomers in VD rats. Apelin-13 reduces the level of APJ homodimers and leads to the proliferation of endogenous neural stem cells in the hippocampal dentate gyrus area, suggesting that it has a neuroprotective role. In this study, we established a rat and cellular oxygen-glucose deprivation/reoxygenation VD model to investigate the impact of APJ homodimerisation on autophagy. We found that APJ homodimers protect against VD by inhibiting autophagy through the Gαq and PI3K/Akt/mTOR pathways upon Gαi signalling, both in vivo and in vitro. This discovery provides a promising therapeutic target for chronic cerebral ischaemia-reperfusion diseases and an experimental foundation for the development of drugs that target APJ homodimers.
摘要：
血管性痴呆(VD),进行性血管性认知障碍，以存在脑灌注不足为特征，血脑屏障通透性增加，和白质病变。尽管目前的治疗策略主要集中在高血压等危险因素上，糖尿病,还有心脏病,目前缺乏有效的靶向治疗,VD的潜在机制尚不清楚.我们以前发现Apelin受体（APJ），它们是G蛋白偶联受体（GPCRs），可以同二聚化并产生与VD大鼠中APJ单体不同的信号。Apelin-13降低APJ同二聚体水平,导致海马齿状回区内源性神经干细胞增殖,表明它有神经保护作用.在这项研究中,我们建立了大鼠和细胞氧糖剥夺/复氧VD模型，以研究APJ同源二聚体对自噬的影响。我们发现APJ同二聚体通过Gαq和PI3K/Akt/mTOR通路抑制自噬来保护VD，体内和体外。这一发现为慢性脑缺血再灌注疾病提供了有希望的治疗靶标，并为开发靶向APJ同源二聚体的药物提供了实验基础。
