PSMC5介导小胶质细胞功能状态参与AD病理进程的机制研究

小胶质细胞过度激活致慢性神经炎症是AD的重要发病机制之一，但神经炎症参与AD，小胶质细胞被活化引起过度炎症反应的关键启动机制，目前尚不明确。近期《Nature》发表：在突变tau蛋白作用下，小胶质细胞出现老化，其表型改变，生理功能障碍，炎症反应增强。我们前期研究揭示：靶向抑制PSMC5通过抑制TLR4介导的NF-κB通路，负性调节慢性神经炎症，维持中枢神经网络的平衡，改善AD的进展，但其抑制小胶质细胞过度活化的关键启动机制尚不明。据此推测，调控小胶质细胞的功能状态可能是抑制小胶质细胞被过度活化的突破口，靶向抑制PSMC5可能通过抑制小胶质细胞的老化，从而改善AD的进展。项目拟从分子、细胞、动物水平揭示Aβ沉积、小胶质细胞老化与神经炎症间的关系，阐明PSMC5介导小胶质细胞老化参与AD病理进程的分子机制。这将进一步拓展AD的发病机制，明确靶向抑制PSMC5可能是干预AD的一个潜在治疗靶点。

Accumulating evidence suggests that neuroinflammation plays important roles in the development of Alzheimer’s disease (AD). The neuroinflammatory response includes the activation of microglia, which results in a phagocytic phenotype, and the subsequent release of inflammatory mediators such as cytokines, enzymes, adhesion molecules, and free radicals. The suppression of microglia activation and release of inflammatory mediators are important direction in the prevention and treatment of AD. However, neuroinflammation is involved in the pathogenesis of AD. Why are the microglia activated and how are the activated microglia that cause neuroinflammation? The key initial mechanism has not yet been clear. Recently, a paper has been published in 《Nature》 reporting that the neurons do not senile under the condition of mutated tau proteins, while the microglia appear senile. In addition, the phenotype of aging microglia is changed and the physiological function is impaired which are associated with continuous release of pro-inflammatory factors. . Our previous studies revealed that targeted inhibition of PSMC5 (26S proteasome regulatory subunit 8) negatively regulates chronic neuroinflammation, maintains the balance of central nervous network and improves the progress of AD by inhibiting neuroinflammation through TLR-4-mediated NF-kB pathway. However, the key mechanism of PSMC5 knockdown on microglia activation is still unclear. Therefore, it is suggested that the regulation of the functional state of microglia may be critical for inhibition of neuroinflammation through inhibiting activation of microglia, and the targeted inhibition of PSMC5 may improve the progress of AD by inhibiting the aging of microglia.. The purpose of this project is to reveal the relationship between Aβ deposition, microglia aging and neuroinflammation. We’ll elucidate the molecular mechanism of siRNA PSMC5-mediated microglia on aging in the pathogenesis of AD through the molecular, cellular and animal levels. This project will further explore the pathogenesis of AD, and clarify whether regulation of PSMC5 is a potential therapeutic target for the intervention of AD and provide new ideas for the prevention and treatment of AD.