Summary: Sevoflurane, an anesthetic, causes tau to leave neurons and enter microglia. This stimulates the production of interleukin-6, leading to inflammation and cognitive impairment.
Source: Mass General
During the development and progression of Alzheimer’s disease, a protein called 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–immune cells that reside in the brain–are thought to be involved in this process by producing an inflammatory molecule called 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 this current study, the team developed a novel method to measure tau levels, called 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, an instructor in the Department of Anesthesia, Critical Care and Pain Medicine (DACCPM) at MGH.
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,” says senior author Zhongcong Xie, MD, PhD, director of the Geriatric Anesthesia Research Unit in the DACCPM. “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,” says co-lead author Yuanlin Dong, MD, a research fellow in the department.
Another inhaled anesthetic called desflurane did not have the same effects as sevoflurane.
“Our results 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,” says Xie.
“We hope this work will lead to more research on anesthesia, tau proteins, and Alzheimer’s disease pathology that will ultimately improve care for patients.”
Additional co-authors are Lining Huang, MD, PhD, MGH DACCPM and Hebei Medical University, China; Fang Fang, MD, PhD, MGH DACCPM and Fudan University, China; Guang Yang, PhD, Columbia University Medical Center; Rudolph E. Tanzi, PhD, MassGeneral Institute for Neurodegenerative Disease; Yiying Zhang, MD, PhD, MGH DACCPM; and Qimin Quan, PhD, Rowland Institute of Harvard University and NanoMosaic.
Funding: The study was supported by the National Institutes of Health, including both the National Institutes of 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
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. However, the mechanisms and downstream consequences of tau trafficking remain largely unknown.
We hypothesized that tau traffics from neurons to microglia via extracellular vesicles (EVs), leading to IL-6 generation and cognitive impairment. We assessed mice and neurons treated with anesthetics sevoflurane and desflurane, and applied nanobeam-sensor technology, an ultrasensitive method, to measure tau/p-tau amounts. Sevoflurane, but not desflurane, increased tau or p-tau amounts in blood, neuron culture medium, or EVs.
Sevoflurane increased p-tau amounts in brain interstitial fluid. Microglia from tau knockout mice took up tau and p-tau when treated with sevoflurane-conditioned neuron culture medium, leading to IL-6 generation. Tau phosphorylation inhibitor lithium and EVs generation inhibitor GW4869 attenuated tau trafficking. GW4869 mitigated sevoflurane-induced cognitive impairment in mice.
Thus, tau trafficking could occur from neurons to microglia to generate IL-6, leading to cognitive impairment.