血脑屏障功能障碍促进阿尔茨海默病的新机制：PDGF-BB/PDGFRβ/lncRNA PAT1介导的周细胞缺失

PDGF-BB/PDGFRβ通路抑制所致周细胞缺失和血脑屏障（BBB）功能障碍是阿尔茨海默病（AD）的重要发病机制，长链非编码RNA（lncRNA）在其中的作用未见报道。申请者发现lncRNA PAT1在AD样本中显著低表达且和PDGF-BB表达正相关，体外实验发现PDGF-BB通过PAT1促进周细胞增殖，周期蛋白P15和P57表达上调，预测两者启动子区有PRC2复合物潜在结合位点。据此推测：在BBB功能障碍导致AD过程中，PDGF-BB下调而抑制lncRNA PAT1表达，进而干预PRC2复合物介导的P15和P57转录，导致周细胞增殖障碍。本研究通过体内外功能实验探索PDGF-BB/lncRNA PAT1信号轴在周细胞缺失、BBB功能障碍在AD发病中的作用，在分子水平阐明lncRNA PAT1被PDGF-BB活化，介导PRC2转录调控P15和P57的作用机制，为AD的诊治提供新的思路。

Pericyte cell loss and blood-brain barrier (BBB) dysfunction caused by PDGF-BB/PDGFRβ pathway inhibition is an important pathogenesis of Alzheimer's disease (AD). The role of long-chain non-coding RNA (lncRNA) within has not been reported. In the previous work, we found that lncRNA PAT1 was significantly down-regulated in AD samples and up-regulated by PDGF-BB/PDGFRβ pathway. LncRNA PAT1 promoted pericyte proliferation, and the mechanism may be related to P15 and P57 transcriptional regulation. We hypothesize that, in the process of BBB dysfunction leading to AD, lncRNA PAT1 expression is inhibited by PDGF-BB/PDGFRβ signaling loss, which leads to inhibition of PRC2 complex-mediated P15 and P57 transcription, pericyte cell proliferation disorder and loss. This study will focus on the role of lncRNA PAT1 in pericyte cell loss, BBB dysfunction and AD pathogenesis, in vitro and in vivo, and elucidate the mechanism by which lncRNA PAT1 is activated by PDGF-BB/PDGFRβ pathway and transcriptionally regulates P15 and P57. This project would provide new insights for the diagnosis and treatment of AD.