In the Feb. 7 Journal of Neuroscience, researchers from Massachusetts General Hospital (MGH) and colleagues describe how isoflurane may set off a process in which A-beta generation and apoptosis interact with and magnify each other. Since this work was done in cell cultures, it is unknown whether the findings reflect a possible effect of the anesthetic on human brains.
"Our studies have shown that isoflurane may induce a vicious cycle of apoptosis, amyloid-beta generation, and further rounds of apoptosis leading to cell death," says Zhongcong Xie, MD, PhD, of the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND), the study's lead author. "If future studies support these findings, they suggest that caution be used in choosing this anesthetic for elderly patients, who already are at increased risk for Alzheimer's and for postoperative cognitive dysfunction." Xie is also associated with the MGH Department of Anesthesia and Critical Care.
Alzheimer's disease is characterized by plaques within the brain of amyloid-beta protein (A-beta), which is toxic to brain cells. A-beta is formed when the larger amyloid precursor protein (APP) is clipped by two enzymes -- beta-secretase, also known as BACE, and gamma-secretase -- to release the A-beta fragment. Normal processing of APP by an enzyme called alpha-secretase produces an alternative, non-toxic protein.
Some studies have indicated that general anesthesia may increase the risk of developing Alzheimer's disease. It also is known that a small but significant number of surgical patients experience a form of dementia in the postoperative period, but there is insufficient evidence of a direct connection between anesthesia and the risk of dementia. Previous articles -- including a recent report from the same research team -- have shown that isoflurane increases both A-beta generation and apoptosis in several types of cultured cells. The current study was designed to investigate the relationship between isoflurane-induced apoptosis and A-beta generation.
In a series of experiments, the researchers first found that applying isoflurane to cultured neural cells increased the activation of the enzyme caspase -- a key player in a pathway leading to apoptosis -- with no change in A-beta generation or APP processing. When they applied isoflurane to neural cells that express APP and had been treated with a caspase inhibitor, the expected changes in APP processing and A-beta generation were significantly reduced, indicating that caspase activation is essential to the pathway leading to A-beta generation and aggregation.
The researchers also found that isoflurane appears to raise levels of the A-beta-releasing enzymes BACE and gamma secretase and that generation of A-beta plaques further increases isoflurane-induced caspase activation. In addition, adding A-beta to neuronal cells that do not express APP also increased caspase activation in response to isoflurane. Overall, the study's results define molecular pathways by which isoflurane induces deposition of A-beta, both directly and via caspase activation, and by which A-beta deposits lead to further caspase activation and apoptosis.
"Even though our findings and those from other studies suggest that isoflurane may affect Alzheimer's pathogenesis, these experiments were performed in cultured cells only," says Rudolph Tanzi, PhD, director of the MGH-MIND Genetics and Aging Research Unit and senior author of the current paper. "We need to conduct in vivo studies before we can determine whether these results might be relevant to the development of delirium or Alzheimer's disease in human patients." Tanzi is a professor of Neurology at Harvard Medical School, where Xie is an assistant professor of Anesthesia. The researchers also plan to investigate whether other anesthetic agents may produce the same results seen with isoflurane, which is the only anesthetic tested in previous studies.
Sue McGreevey | EurekAlert!
WAKE-UP provides new treatment option for stroke patients | International study led by UKE
17.05.2018 | Universitätsklinikum Hamburg-Eppendorf
First form of therapy for childhood dementia CLN2 developed
25.04.2018 | Universitätsklinikum Hamburg-Eppendorf
A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.
The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...
At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.
At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...
There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?
At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...
So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics
Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...
The historic first detection of gravitational waves from colliding black holes far outside our galaxy opened a new window to understanding the universe. A...
02.05.2018 | Event News
13.04.2018 | Event News
12.04.2018 | Event News
25.05.2018 | Life Sciences
25.05.2018 | Interdisciplinary Research
24.05.2018 | Ecology, The Environment and Conservation