Diabetes is strongly linked to the development of Alzheimer’s disease (AD), though the mechanisms for this enhanced risk are unclear. Because vascular inflammation is a consistent feature of both diabetes and AD, the cerebral microcirculation could be a key target for the effects of diabetes in the brain. The goal of this study is to explore whether brain endothelial cells, injured by diabetes-related insults, glucose and hypoxia, can affect inflammatory and activation processes in microglia in vitro. Human brain microvascular endothelial cells (HBMVECs) were either treated with 5 mM glucose (control), 30 mM glucose (high glucose), exposed to hypoxia, or exposed to hypoxia plus high glucose. HBMVEC-conditioned medium was then used to treat BV-2 microglia. Alterations in microglia phenotype were assessed through measurement of nitric oxide (NO), cytokine production, microglial activation state markers, and microglial phagocytosis. HBMVECs were injured by exposure to glucose and/or hypoxia, as assessed by release of LDH, interleukin (IL)-1β, and reactive oxygen species (ROS). HBMVECs injured by glucose and hypoxia induced increases in microglial production of NO, tumor necrosis factor-α (TNFα) and matrix metalloproteinase (MMP)-9. Injured HBMVECs significantly increased microglial expression of CD11c and CLEC7A, and decreased expression of the homeostatic marker P2RY12. Finally, bead uptake by BV-2 cells, an index of phagocytic ability, was elevated by conditioned media from injured HBMVECs. The demonstration that injury to brain endothelial cells by diabetic-associated insults, glucose and hypoxia, promotes microglial inflammation supports the idea that the cerebral microcirculation is a critical locus for the deleterious effects of diabetes in the AD brain.

糖尿病与阿尔茨海默病 (AD) 的发展密切相关，尽管这种风险增加的机制尚不清楚。由于血管炎症是糖尿病和 AD 的一致特征，因此脑微循环可能是糖尿病对大脑影响的关键目标。本研究的目的是探索受糖尿病相关损伤、葡萄糖和缺氧损伤的脑内皮细胞是否会影响体外小胶质细胞的炎症和活化过程。人脑微血管内皮细胞 (HBMVEC) 用 5 mM 葡萄糖（对照）、30 mM 葡萄糖（高葡萄糖）处理，暴露于缺氧或暴露于缺氧加高葡萄糖。然后使用 HBMVEC 条件培养基治疗 BV-2 小胶质细胞。通过测量一氧化氮 (NO) 评估小胶质细胞表型的变化，细胞因子产生、小胶质细胞活化状态标志物和小胶质细胞吞噬作用。通过 LDH、白细胞介素 (IL)-1β 和活性氧 (ROS) 的释放来评估 HBMVEC 因暴露于葡萄糖和/或缺氧而受损。受葡萄糖和缺氧损伤的 HBMVEC 诱导小胶质细胞产生 NO、肿瘤坏死因子-α (TNFα) 和基质金属蛋白酶 (MMP)-9 的增加。受伤的 HBMVECs 显着增加了 CD11c 和 CLEC7A 的小胶质细胞表达，并降低了稳态标志物 P2RY12 的表达。最后，来自受损 HBMVEC 的条件培养基提高了 BV-2 细胞对珠粒的摄取，这是吞噬能力的一个指标。糖尿病相关损伤、葡萄糖和缺氧对脑内皮细胞的损伤的证明，