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Updated: Nov 5, 2025
An In Vitro Model for Studying Tau Aggregation Using Lentiviral-mediated Transduction of Human Neurons
Published on: May 23, 2019
The anesthetic sevoflurane induces tau trafficking from neurons to microglia
Yuanlin Dong1, Feng Liang1, Lining Huang1,2
1Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
Abstract:
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.
Insights
Sevoflurane anesthesia promotes tau protein spread from neurons to microglia via extracellular vesicles, triggering inflammation and cognitive decline. Inhibiting this process may prevent memory loss in tauopathies.
Area of Science:
- Neuroscience
- Cell Biology
- Pharmacology
Background:
- Tau pathology spreads in a prion-like manner in Alzheimer's disease and tauopathies.
- Mechanisms and consequences of tau trafficking are not fully understood.
Purpose of the Study:
- To investigate if tau traffics from neurons to microglia via extracellular vesicles (EVs).
- To determine if this trafficking leads to Interleukin-6 (IL-6) generation and cognitive impairment.
- To examine the effects of sevoflurane and desflurane on tau trafficking.
Main Methods:
- Assessed mice and neurons exposed to sevoflurane and desflurane.
- Utilized nanobeam-sensor technology to quantify tau and phosphorylated tau (p-tau).
- Investigated microglia uptake of tau and p-tau in vitro.
Main Results:
- Sevoflurane, unlike desflurane, increased tau/p-tau in blood, neuron medium, and EVs.
- Sevoflurane elevated p-tau in brain interstitial fluid.
- Sevoflurane-exposed microglia internalized tau/p-tau, generating IL-6.
- Lithium and GW4869 inhibited tau trafficking.
- GW4869 reduced sevoflurane-induced cognitive impairment.
Conclusions:
- Tau can traffic from neurons to microglia through EVs, inducing IL-6 production.
- This neuroinflammatory pathway contributes to cognitive impairment.
- Targeting tau trafficking may offer therapeutic strategies for tauopathies.
