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, Ph.D., 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, Ph.D., 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.”
Postoperative delirium, one of the most common complications after surgery in older patients [1,2], has been associated with significantly prolonged hospitalizations [3–5], cognitive impairment [1,6,7], functional decline [8,9], development of Alzheimer’s disease and related dementia [7,10–12] and increased mortality [1,13,14].
Specifically, patients with underlying dementia are 2.5 – 4.7 times more likely to develop delirium, and patients with delirium face a 12.5-fold increased incidence of newly diagnosed Alzheimer’s disease and related dementias [10–13]. However, the causes and neuropathogenesis of postoperative delirium remain largely to be determined.
Importantly, evidence indicates that the same surgery under different anesthetics may have different incidences of postoperative neurocognitive disorder [15–18]. Specifically, patients who had surgery to treat cancer under sevoflurane anesthesia had a higher risk of developing delayed neurocognitive recovery than those under propofol anesthesia [17].
Additionally, patients who had radical rectal resection surgery under sevoflurane anesthesia had greater severity of postoperative cognitive dysfunction (POCD) than patients who had the same surgery under propofol anesthesia [18].
Patients carrying the ApoE ɛ 4 alleles were more likely to develop early postoperative cognitive dysfunction after surgery under isoflurane anesthesia [19]. However, the effect of anesthetic type (e.g., inhalation versus intravenous anesthetic) on the incidence, duration and severity of postoperative delirium in patients remains largely unknown.
A randomized study showed that laparoscopic surgery under epidural plus sevoflurane anesthesia was associated with a lower delirium rating scale (DRS) score than under epidural plus propofol anesthesia [20]. Previous studies also showed that the incidence of postoperative delirium in patients who had a gastrectomy, colectomy, or rectectomy under epidural plus propofol anesthesia or sevoflurane anesthesia was 6.9% and 26.7%, respectively [21].
Nevertheless, the potential differences in incidence, duration and severity of postoperative delirium in patients who have surgery under general anesthesia with sevoflurane or propofol remain to be determined. We therefore set up this randomized clinical trial to determine the incidence, duration, and severity of postoperative delirium in older patients who had a total hip replacement (THR) or total knee replacement (TKR) under general anesthesia with sevoflurane or propofol. Notably, there are more than 1 million TKR/THR each year in United States [22].
It is estimated that there will be a significant increase in TKR/THR over the next 15 years, which will bring a heavy economic burden [23, 24]. The long-term objective of our study was to identify the anesthetic(s) associated with shorter duration, lower incidence, and less severity of postoperative delirium in patients. We hypothesized that the patients who had surgery under sevoflurane or propofol anesthesia would demonstrate different incidence duration, and severity of postoperative delirium.
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844419/
More information: Yuanlin Dong et al, The anesthetic sevoflurane induces tau trafficking from neurons to microglia, Communications Biology (2021). DOI: 10.1038/s42003-021-02047-8
