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The Journal of Neuroscience, February 7, 2007, 27(6):1247-1254; doi:10.1523/JNEUROSCI.5320-06.2007

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Neurobiology of Disease
The Inhalation Anesthetic Isoflurane Induces a Vicious Cycle of Apoptosis and Amyloid ß-Protein Accumulation

Zhongcong Xie,^1,2 Yuanlin Dong,^1,2 Uta Maeda,^1,2 Robert D. Moir,¹ Weiming Xia,³ Deborah J. Culley,⁴ Gregory Crosby,⁴ and Rudolph E. Tanzi¹

¹Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, and Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129-2060, ²Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, and ³Center for Neurologic Diseases and ⁴Department of Anesthesia, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

Correspondence should be addressed to Dr. Rudolph E. Tanzi, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, and Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114 16th Street, C3009, Charlestown, MA 02129-4404. Email: tanzi{at}helix.mgh.harvard.edu

The anesthetic isoflurane has been reported to induce apoptosis and increase Aß generation and aggregation. However, the molecular mechanism underlying these effects remains unknown. We therefore set out to assess whether the effects of isoflurane on apoptosis are linked to amyloid ß-protein (Aß) generation and aggregation. For this purpose, we assessed the effects of isoflurane on ß-site amyloid ß precursor protein (APP)-cleaving enzyme (BACE) and -secretase, the proteases responsible for Aß generation. We also tested the effects of inhibitors of Aß aggregation (iAß5, a ß-sheet breaker peptide; clioquinol, a copper–zinc chelator) on the ability of isoflurane to induce apoptosis. All of these studies were performed on naive human H4 neuroglioma cells as well as those overexpressing APP (H4-APP cells). Isoflurane increased the levels of BACE and -secretase and secreted Aß in the H4-APP cells. Isoflurane-induced Aß generation could be blocked by the broad-based caspase inhibitor Z-VAD. The Aß aggregation inhibitors, iAß5 and clioquinol, selectively attenuated caspase-3 activation induced by isoflurane. However, isoflurane was able to induce caspase-3 activation in the absence of any detectable alterations of Aß generation in naive H4 cells. Finally, Aß potentiated the isoflurane-induced caspase-3 activation in naive H4 cells. Collectively, these findings suggest that isoflurane can induce apoptosis, which, in turn, increases BACE and -secretase levels and Aß secretion. Isoflurane also promotes Aß aggregation. Accumulation of aggregated Aß in the media can then promote apoptosis. The result is a vicious cycle of isoflurane-induced apoptosis, Aß generation and aggregation, and additional rounds of apoptosis, leading to cell death.

Key words: Alzheimer's disease; APP; Aß; apoptosis; anesthesia; isoflurane

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Received Dec. 8, 2006; revised Dec. 27, 2006; accepted Dec. 30, 2006.

Correspondence should be addressed to Dr. Rudolph E. Tanzi, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, and Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114 16th Street, C3009, Charlestown, MA 02129-4404. Email: tanzi{at}helix.mgh.harvard.edu

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