17 February 2007. Recent studies have raised the troubling possibility that widely used inhaled anesthetics might exacerbate amyloid pathology. Although there is no hard data in human studies to support this idea, work from Roderic Eckenhoff and colleagues at the University of Pennsylvania in Philadelphia showed several years ago that some anesthetics enhanced the oligomerization of Aβ peptides in vitro (Eckenhoff et al., 2004). After that, studies from Rudy Tanzi’s lab showed that one anesthetic, isoflurane, increased Aβ production and induced apoptosis in cultured neuroglioma cells that overexpress the amyloid precursor protein (Xie et al., 2006). Now, in a follow-up paper published in the Journal of Neuroscience, Tanzi and Zhongcong Xie probe the link between Aβ and apoptosis in response to isoflurane in these cells. Their results suggest that while isoflurane-induced apoptosis doesn’t require Aβ production, the presence of Aβ might well exacerbate it.
This line of study stems from a hypothesis that post-operative cognitive dysfunction, a confused state associated with surgery and anesthesia that is common in elders, might be related to Alzheimer disease and Aβ pathology (Xie et al., 2006). While this work, all carried out in vitro, cannot prove that is the case, it certainly calls for more study of the effects of anesthesia on elderly patients.
From their previous work, Xie and colleagues knew that isoflurane induced apoptosis (including caspase 3 activation), altered APP processing, and increased production of Aβ in human neuroglioma cells overexpressing APP. Their new results show that blocking caspase activation with the general inhibitor Z-VAD partially inhibited the changes in APP processing, suggesting that induction of apoptosis might be leading to increased Aβ production.
To test whether increased Aβ production and aggregation might trigger further rounds of apoptosis, the investigators treated cells with two different aggregation inhibitors. Both compounds, a peptide inhibitor of β-sheet formation and clioquinol, partially blocked the activation of caspase 3 by isoflurane.
However, when they looked at cells that did not overexpress APP, the results were slightly different. In the parental neuroglioma cell line, isoflurane induced caspase 3 activation and apoptosis, without any detectable change in APP processing or Aβ production. But when they added Aβ to the cells, as expected they saw activation of caspase 3. The combination of Aβ and isoflurane showed increased caspase 3 activation.
From these results, the researchers raise the possibility that isoflurane could trigger a “vicious cycle” of Aβ-related pathology. The anesthetic increases apoptosis, which leads to increased Aβ secretion. Isoflurane also promotes Aβ aggregation, which further increases apoptosis, and production of Aβ. One caveat is that the scientists only observed increased Aβ in the APP overexpressing cells, where they also detected a modest increase in the levels of β-secretase protein and in the γ-secretase subunit nicastrin. But the results of adding Aβ to cells with normal APP suggests that if there is Aβ already around (as is often the case in elderly brain), isoflurane might enhance its toxicity.
Post-surgical complications for many elderly patients include confusion and cognitive impairment. A hot question in the gerontology field right now is whether the acute delirium that often besets hospitalized elders is related to Alzheimer dementia, or can precipitate a decline into dementia. The risk factors for AD and for developing confusion during acute illness are similar, and include carrying the ApoE4 allele (Ely et al., 2007). In addition, one study showed that elders who experience post-surgical delirium are more likely to be diagnosed with dementia in the following years than those who come through hospitalization clear-headed (Wacker et al., 2006). Though far from conclusive, these tidbits together raise the possibility that post-surgery delirium might represent an early glimpse of Aβ pathology, or a precipitating event leading to the clinical onset of AD in older patients.—Pat McCaffrey.
Xie Z, Dong Y, Maeda U, Moir RD, Xia W, Culley DJ, Crosby G, Tanzi RE. The inhalation anesthetic isoflurane induces a vicious cycle of apoptosis and amyloid beta-protein accumulation. J Neurosci. 2007 Feb 7;27(6):1247-54. Abstract