Targeting age and gender-dependent microglia-mediated mechanisms underlying postoperative cognitive impairment for treatment of delirium in the elderly

妄想是老年人大手术后常见且重要的认知并发症。病因学 精神错乱的异质性及其潜在的病理生理机制阻碍了预防和治疗的进展。 治疗。全身性和中枢神经系统炎症作为 精神错乱的病理生理学基础。全身性炎症诱导神经炎症--主要由 脑内常驻免疫细胞，如小胶质细胞、循环中的促炎细胞因子和脑渗透 单核细胞--导致急性认知功能障碍。最近的研究报告了与年龄相关的异质性 小胶质细胞的分子表型与阿尔茨海默病等脑部疾病的小鼠模型有关。 这些发现强调了小胶质细胞介导的神经炎症是一种潜在的与年龄相关的病理生理机制。 精神错乱的潜在机制。另一项研究强调了小胶质细胞在控制中的重要性。 细胞外谷氨酸，一种参与正常认知和精神错乱的神经递质。小胶质细胞发挥重要作用 在谷氨酸/谷氨酰胺循环中的作用，是谷氨酸释放和清除的关键调节器 神经炎。激活的小胶质细胞过度释放谷氨酸导致兴奋性毒性和神经毒性 损坏。谷氨酰胺酶是谷氨酸合成的主要酶，对突触谷氨酸有贡献 谷氨酸的释放和胶质细胞的产生。6-重氮-5-氧代-L去亮氨酸(DON)，是一种谷氨酰胺类似物，其作用是 谷氨酰胺酶抑制剂和阻止激活的小胶质细胞释放谷氨酸，已显示出促进认知的功效 在神经炎症的各种疾病模型中。我们最近开发了口服DON前药。 (JHU-083)，旨在提高中枢神经系统的渗透率。值得注意的是，JHU-083有效地将DON传递到大脑和 JHU-083抑制应激诱导的小胶质细胞谷氨酰胺酶活性和细胞因子的诱导，使应激正常化。 诱导性行为。因此，我们假设小胶质细胞谷氨酰胺酶活性的上调可能有助于 JHU-083对年龄相关性术后认知障碍的影响及对谷氨酰胺酶的抑制作用可能逆转 腹部手术诱导小胶质细胞激活，可能减轻术后认知障碍。在……里面 在这项研究中，我们将确定年龄和性别相关的术后认知障碍。我们将决定 术后年龄和性别相关的小胶质细胞转录组景观和共同的改变。 谷氨酰胺酶和炎症基因的调控分子环境。我们还将确定是否 年龄相关的术后神经炎和认知障碍需要小胶质细胞的激活。 最后，我们将确定JHU-083是否改善与年龄相关的术后认知障碍 并使谷氨酰胺酶活性、小胶质细胞激活和神经炎症恢复正常。我们的研究将揭示年龄- 与腹部手术相关的小胶质细胞炎症易感性是其病理生理学基础 术后认知障碍。我们的发现还将提供证据表明小胶质细胞中的谷氨酰胺酶是一种 治疗老年人术后与精神障碍相关的认知障碍的潜在药物靶点。

Delirium is a common and significant cognitive complication after major surgery in older people. The etiological heterogeneity of delirium and luck of its underlying pathophysiology hampers advances in prevention and treatment. Systemic and CNS inflammation have gained greater attention as components of the pathophysiology underlying delirium. Systemic inflammation induces neuroinflammation – largely regulated by brain resident immune cells such as microglia, and circulating pro-inflammatory cytokines and brain-infiltrating monocytes – resulting in acute cognitive dysfunction. Recent studies reported age-dependent heterogeneous microglial molecular phenotypes linked to mouse models of brain diseases such as Alzheimer's disease. These findings highlight microglia-mediated neuroinflammation as a potential age-related pathophysiological mechanism underlying delirium. Another line of research underscores the importance of microglia in the control of extracellular glutamate, a neurotransmitter involved in normal cognition and delirium. Microglia play essential roles in the glutamate/glutamine cycle and are key regulators of glutamate release and clearance under neuroinflammation. Exaggerated release of glutamate by activated microglia leads to excitotoxicity and neural damage. Glutaminase is the primary enzyme for glutamate synthesis, contributing to synaptic glutamate release and glial production of glutamate. 6-diazo-5-oxo-L-norleucine (DON), a glutamine analog that acts as a glutaminase inhibitor and blocks glutamate release from activated microglia, has shown pro-cognitive efficacy in various disease models of neuroinflammation. We have recently developed orally available prodrugs of DON (JHU-083), designed to improve CNS penetration. Notably, JHU-083 effectively delivers DON to the brain and JHU-083 inhibits stress-induced microglial glutaminase activity and cytokine induction, normalizing stress- induced behaviors. Hence, we hypothesize that upregulation of microglial glutaminase activity may contribute to age-related postoperative cognitive impairments, and inhibition of glutaminase by JHU-083 may reverse abdominal surgery-induced microglia activation, which may alleviate postoperative cognitive impairments. In this study, we will identify age and gender-dependent postoperative cognitive impairments. We will determine age and gender-dependent postoperative alterations in the microglial transcriptome landscape and co- regulated molecular environment of glutaminase and inflammatory genes. We will also determine whether microglia activation is required for age-dependent postoperative neuroinflammation and cognitive impairments. Finally, we will determine whether JHU-083 ameliorates age-dependent postoperative cognitive impairments and normalizes glutaminase activity, microglia activation, and neuroinflammation. Our study will reveal age- related microglial inflammatory vulnerability to abdominal surgery that underlies the pathophysiology of postoperative cognitive impairments. Our findings will also provide evidence that glutaminase in microglia is a potential drug target for postoperative cognitive impairments associated with delirium in the elderly.