Approximately 8.5 million Alzheimer's disease (AD) patients and a much greater number of senior patients who are vulnerable to AD will need surgical care under anesthesia every year around the world. Anesthesia and surgery have been reported to induce cognitive dysfunction, which AD and senior patients are susceptible to developing. Therefore, it is necessary to identify anesthetics that will ("bad") or will not ("good) promote AD pathogenesis and cognitive dysfunction, and to elucidate the underlying mechanisms. Our current R01 has established the system and shown the difference between the commonly used anesthetics isoflurane, desflurane, nitrous oxide and propofol on neurotoxicity. However, the underlying mechanisms remain unknown. Consistent with the findings that compounds with low chemical bond energy are unstable and thus can more easily form free radicals (FRs), which contribute to reactive oxygen species (ROS), our preliminary data have shown that isoflurane (with lower bond energy in "Chloride-Carbon") but not desflurane (with higher bond energy in "Fluoride-Carbon"), increases levels of FRs and ROS. In the renewal R01, we will determine whether the difference in bond energy is the molecular basis by which isoflurane, but not desflurane, increases accumulation of FRs and ROS, and induces mitochondrial dysfunction, thereby causing activation of Tau kinase, leading to Tau phosphorylation and consequently learning and memory impairment. We will perform both mechanistic and translational studies by employing chemical and genetic tools through both in vitro (cultured cells, neurons and isolated mitochondria from mice) and in vivo (wild-type, AD transgenic, Tau and cyclophilin D knockout mice) approaches. We will test our hypothesis: isoflurane, but not desflurane, causes mitochondria-associated Tau phosphorylation, which interacts with AD gene mutation-induced Ab elevation, leading to more severe learning and memory impairment in three Specific Aims: 1) to systematically evaluate the effects of isoflurane, desflurane, nitrous oxide and propofol (alone or in combination) on mitochondrial function, Tau levels, and learning and memory in mice;2) to investigate a chemical bond energy-based mechanism, which may elucidate why isoflurane and desflurane have different neurotoxic effects;3) to determine the in vivo cause-effect relationship and targeted interventions using Tau and cyclophilin D knockout mice, FRs scavenge Vitamin C, antioxidant N-acetyl-L-cysteine, and mitochondrial permeability transition pore inhibitor cyclosporine A. This proposal aims at investigating an understudied yet important health topic. The anticipated results would: 1) identify so called "good" and "bad" anesthetic(s) affecting AD pathogenesis and cognitive function in mice;2) elucidate new underlying mechanisms of anesthesia neurotoxicity;and 3) determine the strategy of prevention and treatment. These findings would conceptually advance anesthesia neurotoxicity research and promote more studies, including clinical investigation, and ultimately lead to safer anesthesia care and better postoperative outcomes for AD and senior patients.

Public Health Relevance

Our current R01 studies have established the system and shown that the anesthetic isoflurane, but not desflurane, may promote Alzheimer's disease pathogenesis in vitro and in vivo. The proposed research in this renewal R01 will focus on mechanistic and translational studies. We will (1) identity various anesthetics and anesthesia regimens which will or will not promote Alzheimer's disease pathogenesis and induce impairment of learning and memory in wild-type and transgenic mice;(2) investigate the chemical bond energy-based and mitochondria-associated mechanisms of anesthesia neurotoxicity;and (3) determine the in vivo cause-effect relationship and explore the targeted interventions.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Aging Systems and Geriatrics Study Section (ASG)
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Cole, Alison E
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Massachusetts General Hospital
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Wang, Hui; Xu, Zhipeng; Wu, Anshi et al. (2015) 2-deoxy-D-glucose enhances anesthetic effects in mice. Anesth Analg 120:312-9
Cheng, Baiqi; Zhang, Yiying; Wang, Arthur et al. (2015) Vitamin C Attenuates Isoflurane-Induced Caspase-3 Activation and Cognitive Impairment. Mol Neurobiol 52:1580-9
Shao, Haijun; Zhang, Yiying; Dong, Yuanlin et al. (2014) Chronic treatment with anesthetic propofol improves cognitive function and attenuates caspase activation in both aged and Alzheimer's disease transgenic mice. J Alzheimers Dis 41:499-513
Li, Xiao-Min; Su, Fan; Ji, Mu-Huo et al. (2014) Disruption of hippocampal neuregulin 1-ErbB4 signaling contributes to the hippocampus-dependent cognitive impairment induced by isoflurane in aged mice. Anesthesiology 121:79-88
Xu, Zhipeng; Dong, Yuanlin; Wang, Hui et al. (2014) Peripheral surgical wounding and age-dependent neuroinflammation in mice. PLoS One 9:e96752
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Xu, Zhipeng; Dong, Yuanlin; Wang, Hui et al. (2014) Age-dependent postoperative cognitive impairment and Alzheimer-related neuropathology in mice. Sci Rep 4:3766
Xie, Zhongcong; Swain, Celeste A; Ward, Sarah A P et al. (2014) Preoperative cerebrospinal fluid ?-Amyloid/Tau ratio and postoperative delirium. Ann Clin Transl Neurol 1:319-328
Tao, Guorong; Zhang, Jie; Zhang, Lei et al. (2014) Sevoflurane induces tau phosphorylation and glycogen synthase kinase 3? activation in young mice. Anesthesiology 121:510-27
Ji, MuHuo; Dong, Lin; Jia, Min et al. (2014) Epigenetic enhancement of brain-derived neurotrophic factor signaling pathway improves cognitive impairments induced by isoflurane exposure in aged rats. Mol Neurobiol 50:937-44

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