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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., Using their previously developed nanobeam-sensor technology to detect tau protein in the blood, Yuanlin Dong et al. find that the anaesthetic sevoflurane induces trafficking of tau from neurons to microglia in mice. They further see that microglia can take up tau, leading to Il-6 production, overall bringing new insights into the mechanism of sevoflurane-mediated cognitive impairment.

Postoperative cognitive change (POCC) or postoperative cognitive dysfunction (POCD)1,2 (reviewed in Silverstein et al3 and Terrando et al4) is one of the most common postoperative complications in older adults who have undergone surgery5 and is associated with impairments in daily functioning,6 risk of leaving the labor market prematurely, dependency on social transfer payments,7 and increased morbidity and mortality.7–9 However, at the present time, POCC is a clinical phenomenon and its neuropathogenesis remains largely to be determined; moreover, there have been no biomarker(s) that could identify the risk for the development of POCC. This gap in knowledge has become a barrier that prevents further studies and potential intervention of POCC. β-Amyloid protein (Aβ), including Aβ40 and Aβ2, the key component of senile plaques in patients with Alzheimer disease (AD), and tau, the major protein component of intraneuronal neurofibrillary tangles, are the hallmarks of AD neuropathogenesis (reviewed in Querfurth and LaFerla10). Reduction of Aβ40 and Aβ42 levels and elevation of tau levels in cerebrospinal fluid (CSF) have been reported in AD patients11,12 (reviewed in Holtzman13). Moreover, it has been reported that the Aβ42/tau ratio in CSF can better distinguish AD patients from healthy controls of the same age than Aβ42 or tau alone.12,14 However, whether the Aβ42/tau or Aβ40/tau ratio in CSF is associated with POCC is unknown. Therefore, we performed a prospective investigation to determine whether preoperative CSF Aβ42/tau ratio or Aβ40/tau ratio is associated with individual components, including verbal learning and visual memory, of a cognitive battery designed to evaluate POCC. We hypothesized that CSF Aβ42/tau or Aβ40/tau ratio will be associated with verbal learning and visual memory. The outcomes from this study may serve 2 purposes: (1) to evaluate preoperative CSF Aβ/tau ratio as a potential biomarker of POCC and (2) to promote more studies to determine the role of Aβ and tau in the neuropathogenesis of POCC. We used the term “POCC” instead of “POCD” in the article because the studies did not assess the potential association between CSF Aβ40/tau or Aβ42/tau ratio and cognitive function in participants without surgery. Therefore, we were unable to determine the true incidence of POCD because the change scores could be confounded by the learning effects of the participants.

Anesthetic isoflurane has been shown to promote Alzheimer’s disease (AD) neuropathogenesis by inducing caspase activation and accumulation of β-amyloid (Aβ). Phosphorylation of tau protein is another important feature of AD neuropathogenesis. However, the effects of isoflurane on phosphorylated tau levels remain largely to be determined. We therefore set out to determine whether isoflurane can increase phosphorylated tau levels. 5 to 8 month-old wild-type and AD transgenic mice [B6.Cg-Tg (APPswe, PSEN1dE9)85Dbo/J] were treated with 1.4% isoflurane for two hours. The mice brain tissues were harvested at six, 12 and 24 hours after the anesthesia. For the in vitro studies, primary neurons from wild-type and the AD transgenic mice were exposed to 2% isoflurane for six hours, and were harvested at the end of anesthesia. The harvested brain tissues and neurons were subjected to Western blot analysis by which the levels of phosphorylated tau protein at Serine 262 (Tau-PS262) were determined. Here we show that the isoflurane anesthesia increased Tau-PS262 levels in brain tissues and primary neurons from the wild-type and AD transgenic mice. Moreover, the isoflurane anesthesia may induce a greater increase in Tau-PS262 levels in primary neurons and brain tissues from the AD transgenic mice. Finally, caspase activation inhibitor Z-VAD and Aβ generation inhibitor L-685,458 attenuated the isoflurane-induced increases in Tau-PS262 levels. In conclusion, clinically relevant isoflurane anesthesia increases phosphorylated tau levels, which may result from the isoflurane-induced caspase activation and Aβ generation. These findings will promote more studies to determine the effects of anesthetics on tau phosphorylation.