The sevoflurane anesthetic affect tau spread in the brain to promote Alzheimer’s disease pathology

Significance 

During the development and progression of Alzheimer’s disease, tau accumulates and spreads in the brain. Understanding the mechanisms behind tau spread and its consequences may point to new prevention and treatment strategies for Alzheimer’s disease and other forms of dementia. New insights now come from research that was led by investigators at Massachusetts General Hospital (MGH) and involves an anesthetic known to affect cognitive function. The findings are published in Communications Biology.

The scientists note that inflammation plays an important role in Alzheimer’s disease, and microglia are thought to be involved in this process by producing an inflammatory molecule interleukin-6. To see if tau stimulates microglia to drive the development of Alzheimer’s disease pathology, the MGH investigators and their colleagues conducted experiments with an inhaled anesthetic called sevoflurane. Their previous work showed that sevoflurane can cause a change (specifically, phosphorylation, or the addition of phosphate) to tau that leads to cognitive impairment in mice. Other researchers have also found that sevoflurane and certain other anesthetics may affect cognitive function.

In a new study, the team developed a novel method to measure tau levels, using nanobeam-sensor technology. The nanobeam sensor is ultrasensitive, requires a small volume, and can measure low concentrations of molecules, including tau and phosphorylated tau. The group conducted experiments in mice and cells and discovered that sevoflurane causes tau to leave neurons and enter microglia, where it stimulates the cells’ production of interleukin-6, which in turn leads to inflammation and cognitive impairment. The trafficking of tau from neurons to microglia involves tau phosphorylation and membrane-bound carriers called extracellular vesicles that are released from cells.

These data demonstrate anesthesia-associated tau spreading and its consequences, This tau spreading could be prevented by inhibitors of tau phosphorylation or extracellular vesicle generation. Sevoflurane did not increase the release of lactate dehydrogenase, a molecule with a similar size and weight as tau, from neurons. This finding indicates that neuronal cell membranes and cell viability were not compromised by sevoflurane treatment and that the sevoflurane-induced leaking of tau was not a passive process.

Another inhaled anesthetic called desflurane did not have the same effects as sevoflurane. The authors’ findings suggest that the anesthetics sevoflurane and desflurane may have different impacts on tau phosphorylation and tau spreading. More important, sevoflurane may be used as a clinically relevant tool to study tau spreading and its underlying mechanisms, The research team hope the work will lead to more studies on anesthesia, tau proteins, and Alzheimer’s disease pathology that will ultimately improve care for patients.

The sevoflurane anesthetic affect tau spread in the brain to promote Alzheimer's disease pathology - Medicine Innovates

About the author

Zhongcong Xie, MD, PhD

Attending anesthesiologist and Henry Knowles Beecher Professor of Anesthesia in Massachusetts General Hospital and Harvard Medical School

Research Interests: Neurotoxic potential of anesthetics, Alzheimer’s disease (AD) neuropathogenesis, postoperative cognitive dysfunction (POCD), and postoperative delirium (POD)

Dr. Zhongcong Xie has been a physician-scientist at Massachusetts General Hospital (MGH) and Harvard Medical School since 2000, and has made significant impact to the anesthesia and anesthesia neurotoxicity research. Dr. Xie graduated from Xuzhou Medical University in China and received a Ph.D. degree from Wayne State University, Detroit, Michigan in 1994.  He was a postdoctoral fellow in Harvard Medical School before joining the anesthesia residency program at MGH in 1997. Research in Dr. Xie’s laboratory focuses on determining the neuropathogenesis of AD, as well as POCD and POD, a deficit of learning, memory and attention following anesthesia and surgery. He assesses the potential neurotoxicity of anesthesia, surgery, and other perioperative factors in vitro and in vivo. Specifically, Dr. Xie investigates the effects of anesthetics, surgery, pain and sleep deficiency on apoptosis, mitochondrial function, beta-amyloid protein metabolism, Tau protein phosphorylation and neuroinflammation in cultured cells, animals and humans, employing cellular, molecular, and behavioral approaches. Dr. Xie is the fellow of American Society of Anesthesiologist and elected member of Association of University Anesthesiologists.

Reference

Yuanlin Dong, Feng Liang, Lining Huang, Fang Fang, Guang Yang, Rudolph E. Tanzi, Yiying Zhang, Qimin Quan, Zhongcong Xie. The anesthetic sevoflurane induces tau trafficking from neurons to microglia. Communications Biology, 2021; 4 (1) DOI: 10.1038/s42003-021-02047-8

Go To Communications Biology

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