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

谵妄是老年人大手术后常见且重要的认知并发症。病因 谵妄的异质性及其潜在的病理生理学阻碍了预防和 治疗全身性和CNS炎症作为炎症的组成部分已经获得了更大的关注。 精神错乱的病理生理学全身性炎症诱导神经炎症-主要受 脑驻留免疫细胞，如小胶质细胞，和循环促炎细胞因子和脑浸润 单核细胞-导致急性认知功能障碍。最近的研究报道了年龄依赖性异质性 小胶质细胞分子表型与脑疾病如阿尔茨海默病的小鼠模型有关。 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年龄相关的病理生理学机制。 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脑损伤中的重要性。 细胞外谷氨酸盐，一种参与正常认知和谵妄的神经递质。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剂， 神经炎症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。 损害谷氨酰胺酶是谷氨酸合成的主要酶，有助于突触谷氨酸 谷氨酸的释放和神经胶质的产生。6-重氮-5-氧代-L-正亮氨酸（DON），一种谷氨酰胺类似物， 谷氨酰胺酶抑制剂和阻断谷氨酸从激活的小胶质细胞释放，已显示出促认知功效 神经炎症的各种疾病模型中。我们最近开发了DON的口服前药 （JHU-083），旨在改善CNS渗透。值得注意的是，JHU-083有效地将DON递送到大脑， JHU-083抑制应激诱导的小胶质细胞转氨酶活性和细胞因子诱导， 诱导行为。因此，我们假设小胶质细胞转氨酶活性的上调可能有助于 与年龄相关的术后认知障碍，JHU-083对转氨酶的抑制可能会逆转 腹部手术诱导的小胶质细胞活化，这可能会减轻术后认知障碍。在 在这项研究中，我们将确定年龄和性别依赖的术后认知障碍。我们将确定 年龄和性别依赖性的术后小胶质细胞转录组变化， 调节转氨酶和炎症基因的分子环境。我们还将确定 小胶质细胞活化是年龄依赖性术后神经炎症和认知障碍所必需的。 最后，我们将确定JHU-083是否改善年龄依赖性术后认知障碍 并使转氨酶活性、小胶质细胞活化和神经炎症正常化。我们的研究将揭示年龄- 相关的小胶质细胞炎症对腹部手术的脆弱性，这是 术后认知障碍我们的研究结果也将提供证据表明，在小胶质细胞中的转氨酶是一种免疫抑制剂。 老年人谵妄相关术后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.