# General Anesthesia and Alzheimer's Disease Neuropathogenesis

> **NIH NIH RF1** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $1,918,055

## Abstract

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 ultimate...

## Key facts

- **NIH application ID:** 10119369
- **Project number:** 9RF1AG070761-10A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Zhongcong Xie
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,918,055
- **Award type:** 9
- **Project period:** 2020-09-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10119369

## Citation

> US National Institutes of Health, RePORTER application 10119369, General Anesthesia and Alzheimer's Disease Neuropathogenesis (9RF1AG070761-10A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10119369. Licensed CC0.

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