Several studies have suggested that Alzheimer's disease (AD), one of the most common forms of dementia, might be facilitated by anesthesia and surgery. Our recent research showed that the commonly used inhalational anesthetic isoflurane could induce caspase activation and apoptosis, which in turn increases generation of amyloid 2-protein (A2), the key component of senile plaques in AD patients. These findings could have potential clinical importance since increased A2 generation and apoptosis by anesthesia could conceivably serve to trigger or exacerbate the development of AD. However, the up-stream underlying mechanisms and the down-stream consequences of the isoflurane- induced apoptosis and A2 generation (apoptosis/A2 generation) remain largely unknown. Consistent with the notions that excessive calcium can trigger or contribute to apoptosis and isoflurane can affect synaptic function, our preliminary studies have shown that isoflurane can 1) induce apoptosis/A2 generation, 2) enhance cytosolic calcium levels, and 3) reduce surface NMDA receptors in cortical neurons of naove mice. Thus, our main hypothesis is that isoflurane enhances cytosolic calcium levels to induce apoptosis/A2 generation, leading to synaptic NMDA receptor endocytosis. We will employ chemical and genetic tools through both in vitro and in vivo approaches to accomplish three Specific Aims: 1) to characterize effects of isoflurane on apoptosis/A2 generation;2) to define whether the alterations in cytosolic calcium levels are associated with isoflurane-induced apoptosis/A2 generation;and 3) to determine the effects of isoflurane on synaptic NMDA receptor endocytosis. The proposed research aims to extend our recent findings that isoflurane induces apoptosis/A2 generation to further determine the underlying mechanisms and their effects on synaptic NMDA receptor endocytosis. The data generated in this project would provide novel information regarding the mechanisms of isoflurane- induced apoptosis/A2 generation and their contribution to the impairment of NMDA receptor-mediated synaptic function. The results of this study may ultimately guide researchers and clinicians to design safer anesthetics and to provide better anesthesia care for patients, particularly senior and AD patients.

Public Health Relevance

Our recent research showed that anesthetic isoflurane induces apoptosis and increases the generation of amyloid-2 protein (A2). In the proposed research we will further characterize these effects and determine their up-stream mechanisms and down-stream consequences.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM088801-05
Application #
8400898
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Cole, Alison E
Project Start
2009-02-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
5
Fiscal Year
2013
Total Cost
$334,225
Indirect Cost
$140,336
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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
Wang, H; Dong, Y; Zhang, J et al. (2014) Isoflurane induces endoplasmic reticulum stress and caspase activation through ryanodine receptors. Br J Anaesth 113:695-707
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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