Summary: Sevoflurane, a commonly used inhaled anesthetic, prompts tau protein to move out of neurons and into microglia. This transfer triggers microglial production of interleukin-6, driving inflammation and measurable cognitive decline in experimental models.
Source: Mass General
Tau protein accumulation and its spread across brain cells are central features of Alzheimer’s disease and related tauopathies. Clarifying how tau moves between cells and the downstream effects of that movement could point to new strategies for prevention and treatment of dementia.
Investigators at Massachusetts General Hospital (MGH) have provided new insight into these processes by studying the effects of a widely used anesthetic, sevoflurane. Their results, published in Communications Biology, identify a pathway by which an anesthetic exposure can promote tau transfer from neurons to microglia and amplify inflammatory signaling linked to cognitive impairment.
Inflammation is increasingly recognized as a key component of Alzheimer’s disease. Microglia, the brain’s resident immune cells, can produce inflammatory mediators such as interleukin-6 (IL-6) when activated. The MGH team tested whether tau released from neurons could stimulate microglia to generate IL-6 and thereby contribute to pathology.
Earlier work from the same group showed that sevoflurane exposure leads to phosphorylation of tau, a chemical modification that alters tau’s behavior and has been associated with cognitive deficits in mice. Other investigators have also reported cognitive effects linked to sevoflurane and some other anesthetics, prompting deeper investigation into the underlying mechanisms.
To measure tau and phosphorylated tau (p-tau) at very low concentrations, the researchers developed and applied a novel nanobeam-sensor technology. “The nanobeam sensor is ultrasensitive, requires a small volume, and can measure low concentrations of molecules, including tau and phosphorylated tau,” says co-lead author Feng Liang, MD, PhD, of the Department of Anesthesia, Critical Care and Pain Medicine at MGH.
Using a combination of mouse experiments and cell culture studies, the team found that sevoflurane exposure increases levels of tau and p-tau in the extracellular environment, including in blood, neuron culture medium, and extracellular vesicles (EVs). Importantly, sevoflurane—but not the anesthetic desflurane—promoted tau accumulation in brain interstitial fluid and enhanced tau transfer from neurons into microglia.
The data indicate that tau trafficking involves phosphorylation of tau and its packaging into membrane-bound carriers called extracellular vesicles, which are released by neurons and can be taken up by microglia. When microglia internalized tau-containing conditioned medium from sevoflurane-exposed neurons, they increased production of IL-6, linking tau transfer directly to an inflammatory response.
The investigators also provided experimental evidence that the tau transfer and its consequences can be reduced by blocking key steps in the process. A tau phosphorylation inhibitor (lithium) and an inhibitor of extracellular vesicle generation (GW4869) both attenuated tau trafficking in these models. Furthermore, administration of GW4869 lessened sevoflurane-induced cognitive impairment in mice, supporting a causal role for EV-mediated tau transfer in the observed behavioral changes.
Control experiments showed that sevoflurane did not increase release of lactate dehydrogenase (LDH), a protein of similar size to 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,” says co-lead author Yuanlin Dong, MD, a research fellow in the department.
Comparing anesthetics, the team observed that desflurane did not produce the same tau phosphorylation, extracellular release, or subsequent microglial IL-6 induction seen with sevoflurane. “Our results suggest that the anesthetics sevoflurane and desflurane may have different impacts on tau phosphorylation and tau spreading,” says senior author Zhongcong Xie, MD, PhD, director of the Geriatric Anesthesia Research Unit at MGH. “More important, sevoflurane may be used as a clinically relevant tool to study tau spreading and its underlying mechanisms.”
The authors emphasize that these findings provide a model linking anesthetic-induced tau phosphorylation and extracellular vesicle-mediated tau trafficking to microglial activation, IL-6 generation, and cognitive impairment. They hope the work will stimulate further research into how anesthesia, tau biology, and neuroinflammation intersect and how that knowledge can improve patient care.
Additional co-authors include Lining Huang, MD, PhD; Fang Fang, MD, PhD; Guang Yang, PhD; Rudolph E. Tanzi, PhD; Yiying Zhang, MD, PhD; and Qimin Quan, PhD. The study was supported by the National Institutes of Health, including the National Institute on Aging and the Eunice Kennedy Shriver National Institute of Child Health & Human Development.
About this Alzheimer’s disease research news
Source: Mass General
Contact: Sarah Alger – Mass General
Image: The image is in the public domain
Original Research: Open access.
“The anesthetic sevoflurane induces tau trafficking from neurons to microglia” by Yuanlin Dong, Feng Liang, Lining Huang, Fang Fang, Guang Yang, Rudolph E. Tanzi, Yiying Zhang, Qimin Quan & Zhongcong Xie. Communications Biology
Abstract
The anesthetic sevoflurane induces tau trafficking from neurons to microglia
Accumulation and spread of tau in Alzheimer’s disease and other tauopathies occur in a prion-like manner, but the mechanisms and downstream consequences of tau trafficking are not fully understood. The authors hypothesized that neurons release tau packaged in extracellular vesicles that microglia take up, triggering IL-6 production and cognitive impairment. Using mice and neuronal cultures treated with sevoflurane and desflurane, and applying an ultrasensitive nanobeam-sensor to quantify tau and p-tau, they found that sevoflurane—but not desflurane—increased tau and p-tau levels in blood, culture medium, extracellular vesicles, and brain interstitial fluid. Microglia exposed to sevoflurane-conditioned neuronal medium internalized tau and p-tau and generated IL-6. Inhibitors of tau phosphorylation (lithium) and EV generation (GW4869) reduced tau trafficking, and GW4869 ameliorated sevoflurane-induced cognitive deficits in mice. These results support a model in which anesthetic-associated tau trafficking from neurons to microglia stimulates IL-6 production and contributes to cognitive impairment.