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

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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.