Each year around the world, there are about 312.9 million patients, including approximate 8.5 million Alzheimer?s disease (AD) patients and a greater number of senior patients who are vulnerable to AD that need surgery under anesthesia. AD occurs more often in women than in men. Previous studies have shown that anesthetics can promote AD neuropathogenesis, including Tau phosphorylation. However, it is unknown whether or not these effects are dependent on sex. Thus, it is important to identify sex-dependent ?good? and ?bad? anesthetics and to understand their underlying mechanisms. Consistent with the literature that compounds with low bond-dissociation energy are unstable and thus can more easily interact with proteins, our preliminary data have shown that isoflurane and sevoflurane (with a lower clinical bond-dissociation energy), but not desflurane (with a higher clinical bond-dissociation energy), induce Tau phosphorylation and cognitive impairment, which can be attenuated by androgen. In the renewal R01, we will determine whether or not the difference in clinical bond-dissociation energy is the molecular basis by which isoflurane and sevoflurane, but not desflurane, activate GSK3b, the kinase for Tau phosphorylation. Moreover, we will decide whether testosterone (androgen) and estradiol (estrogen) can bind to phosphorylated GSK3b(ser9) to prevent its interaction with Tau and thus to attenuate the anesthetic-induced Tau phosphorylation, Tau trafficking, neuronal dysfunction and cognitive impairment. We will test our hypothesis that anesthetics induce severer cognitive impairments in female mice through a sex-dependent GSK3b activation, Tau phosphorylation and neuronal dysfunction in three Specific Aims: (1) assess the effects of isoflurane, sevoflurane and desflurane on the blood/brain levels of testosterone and estradiol, brain phosphorylated Tau levels and cognitive function in aging (18 - 24 months old), AD transgenic (5XFAD), adult (3 months old) and young (6 days old) mice of both genders; (2) investigate a bond-dissociation energy-based mechanism, which may elucidate why isoflurane, sevoflurane and desflurane have different effects on the interaction of GSK3b and Tau; and how testosterone or estradiol attenuate such interaction; 3) determine the in vivo cause-effect relationship and targeted interventions using estrogen and androgen receptor knockout mice among other methods. This proposal aims at investigating an understudied, yet important health topic. The anticipated results would: 1) identify so called sex-dependent ?good? and ?bad? anesthetic affecting AD neuropathogenesis and cognitive function in mice; 2) elucidate new underlying mechanisms of anesthesia neurotoxicity; and 3) determine the strategies of prevention and treatment. These investigations, including the gender difference studies, would conceptually advance the research on anesthesia neurotoxicity and promote more studies, including clinical investigations, and ultimately lead to the development of personalized anesthesia care (e.g., women vs. men), safer anesthesia practice and better postoperative outcomes for AD and senior patients.
Our last R01 studies have demonstrated that anesthetic isoflurane and sevoflurane, but not desflurane, promote Alzheimer?s disease neuropathogenesis, including Tau phosphorylation. The proposed research in this renewal R01 will (1) identity sex-dependent effects of the anesthetics on Tau phosphorylation and cognitive function in various mice models including aging mice; (2) investigate the bond-dissociation energy and sex hormone associated mechanisms of Tau phosphorylation via the interaction of GSK3b and Tau; and (3) determine the in vivo cause-effect relationship and explore the targeted interventions. These gender difference studies would establish sex-dependent personalized (women vs. men) anesthesia care and provide safer anesthesia care, contributing to prevention strategy for Alzheimer?s disease, consistent with the goal of the National Institute of Health.
