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.
Highlights
Accumulation and spread of tau in Alzheimer’s disease and other tauopathies occur in a prion-like manner
We used anesthetic sevoflurane and desflurane as clinically relevant tools to study tau trafficking in the present study
The data obtained from in vitro and in vivo experiments suggest that tau can exit from neurons upon phosphorylation, travel through both extracellular vesicles (EVs) and non-EVs routes, and enter microglia, leading to generation of interleukin 6 (IL-6)
Summary
Accumulation and spread of tau in Alzheimer’s disease and other tauopathies occur in a prion-like manner. 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 trafficking could occur from neurons to microglia to generate IL-6, leading to cognitive impairment. The conditioned culture medium of microglia obtained from rTg4510 mice contains a higher amount of tau and causes more prion-like seeding of tau than the conditioned culture medium of microglia obtained from wild-type littermates[19,20]. These data indicate that microglia can release tau. The nanobeam-sensor is ultrasensitive (up to femtogram/mL), requires a small volume (30 μL)[29,31], and can measure low concentrations of tau and p-tau
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