. Postoperative cognitive dysfunction (POCD), the most common postoperative complication among geriatric patients and an important research area in the field of Geriatrics and Aging, is associated with substantially increased Alzheimer?s disease (AD) dementia, morbidity, and mortality as well as cost of care. However, the pathogenesis of POCD is still largely unknown, which impede the further studies into POCD. Consistent with the notion that blood CX3CR1+ monocytes and the mitochondria permeability transition pore component Cyclophilin D (CypD) in the brain regulate neuroinflammation and mitochondrial function, our published work and preliminary studies in mice showed that CypD and CX3CR1+ monocytes mediated anesthesia/surgery- and infection-induced cognitive impairment. In addition, CypD levels are higher in brain tissues of AD transgenic (Tg) and aged mice. Thus, the proposed research will assess the effects of anesthesia/surgery on toxicity, including the AD neuropathogenesis-associated changes (e.g., increased CypD levels, neuroinflammation, mitochondrial dysfunction, and neuronal dysfunction). Moreover, we will define a multifactorial model of POCD pathogenesis where the interaction of blood (anesthesia/surgery-induced increases in CX3CR1+ monocytes, the precipitating factor and insulting action) and brain [aging- or AD gene mutation-associated elevation of Cyclophilin D (CypD), the predisposing factor and gating regulation] is needed to cause POCD. The hypothesis of the proposed study is that anesthesia/surgery-induced increases in blood CX3CR1+ monocytes functionally interact with aging- and AD gene mutation-associated enhancement of brain CypD, leading to neuronal dysfunction and POCD-like behavior in mice. We will employ chemical and genetic tools through both neuroimmunology and behavioral approaches to accomplish three Specific Aims: (1) we will assess the effects of anesthesia/surgery on levels of blood CX3CR1+ monocytes and cytokines; brain- infiltrating CX3CR1+ monocytes, neuroinflammation, mitochondrial dysfunction, neuronal dysfunction, and behavior; (2) we will use Cx3cr1CreER/+;R26iDTR/+ and CypD knockout chimeric mice in which CX3CR1+ monocytes, microglia and CypD are depleted so we can assess the roles of blood CX3CR1+ monocytes and brain CypD on the anesthesia/surgery-induced changes; (3) we will determine the effects of a monoclonal antibody for the CX3CR1 ligand CX3CL1; and the protectors of mitochondria (WS635 and Vitamin K2) on the anesthesia/surgery-induced changes. We will include wild-type and adult (4 month-old) mice versus age matched AD Tg and aged (18 month-old) mice (with higher levels of CypD) while employing in vivo cell depletion, in vivo two-photon calcium imaging, Western blot, ELISA, immunohistochemistry, flow cytometry, and behavioral tests. This proposal aims to investigate an understudied topic in innovative systems by testing novel hypotheses, which would ultimately provide better postoperative outcomes for AD and geriatric patients, leading to the development of strategies to prevent AD.

Public Health Relevance

The proposed research will characterize the effects of surgery under different anesthetics on Alzheimer?s disease pathogenesis-associated toxicity (neuroinflammation, mitochondrial dysfunction, neuronal dysfunction, and postoperative cognitive dysfunction-like behavior) in adult, aged and transgenic mice. We will further investigate the role of the blood (CX3CR1+ monocytes) and brain (Cyclophilin D) functional interaction plays on the pathogenesis of postoperative cognitive dysfunction, while seeking to determine novel interventions for the condition. These efforts will ultimately lead to the development of a strategy to prevent Alzheimer?s disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG041274-07
Application #
10003920
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Roberts, Luci
Project Start
2012-09-01
Project End
2024-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
Miao, Huihui; Dong, Yuanlin; Zhang, Yiying et al. (2018) Anesthetic Isoflurane or Desflurane Plus Surgery Differently Affects Cognitive Function in Alzheimer's Disease Transgenic Mice. Mol Neurobiol 55:5623-5638
Shen, Shiqian; Lim, Grewo; You, Zerong et al. (2017) Gut microbiota is critical for the induction of chemotherapy-induced pain. Nat Neurosci 20:1213-1216
Zhang, Ce; Zhang, Yiying; Shen, Yuan et al. (2017) Anesthesia/Surgery Induces Cognitive Impairment in Female Alzheimer's Disease Transgenic Mice. J Alzheimers Dis 57:505-518
Ni, Cheng; Li, Cheng; Dong, Yuanlin et al. (2017) Anesthetic Isoflurane Induces DNA Damage Through Oxidative Stress and p53 Pathway. Mol Neurobiol 54:3591-3605
Lu, Han; Liufu, Ning; Dong, Yuanlin et al. (2017) Sevoflurane Acts on Ubiquitination-Proteasome Pathway to Reduce Postsynaptic Density 95 Protein Levels in Young Mice. Anesthesiology 127:961-975
Yuan, Jing; Cui, Guiyun; Li, Wenlu et al. (2016) Propofol Enhances Hemoglobin-Induced Cytotoxicity in Neurons. Anesth Analg 122:1024-30
Vutskits, Laszlo; Xie, Zhongcong (2016) Lasting impact of general anaesthesia on the brain: mechanisms and relevance. Nat Rev Neurosci 17:705-717
Liang, Feng; Zhang, Yiying; Hong, Wooyoung et al. (2016) Direct Tracking of Amyloid and Tu Dynamics in Neuroblastoma Cells Using Nanoplasmonic Fiber Tip Probes. Nano Lett 16:3989-94
Culley, Deborah J; Flaherty, Devon; Reddy, Srini et al. (2016) Preoperative Cognitive Stratification of Older Elective Surgical Patients: A Cross-Sectional Study. Anesth Analg 123:186-92
Peng, Mian; Zhang, Ce; Dong, Yuanlin et al. (2016) Battery of behavioral tests in mice to study postoperative delirium. Sci Rep 6:29874

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