期刊
JOURNAL OF NEUROSCIENCE
卷 27, 期 6, 页码 1247-1254出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.5320-06.2007
关键词
Alzheimer's disease; APP; A beta; apoptosis; anesthesia; isoflurane
资金
- NIA NIH HHS [R01AG20253, K12AG 000294, P60 AG008812, R01AG 014713] Funding Source: Medline
- NIGMS NIH HHS [K08GM077057] Funding Source: Medline
- NIMH NIH HHS [R01MH 60009] Funding Source: Medline
- NINDS NIH HHS [K08 NS048140] Funding Source: Medline
The anesthetic isoflurane has been reported to induce apoptosis and increase A beta 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 beta-protein (A beta) generation and aggregation. For this purpose, we assessed the effects of isoflurane on beta-site amyloid beta precursor protein (APP)-cleaving enzyme (BACE) and gamma-secretase, the proteases responsible for A beta generation. We also tested the effects of inhibitors of A beta aggregation (iA beta 5, a beta-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 gamma-secretase and secreted A beta in the H4-APP cells. Isoflurane-induced A beta generation could be blocked by the broad-based caspase inhibitor Z-VAD. The A beta aggregation inhibitors, iA beta 5 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 A beta generation in naive H4 cells. Finally, A beta 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 gamma-secretase levels and A beta secretion. Isoflurane also promotes A beta aggregation. Accumulation of aggregated A beta in the media can then promote apoptosis. The result is a vicious cycle of isoflurane-induced apoptosis, A beta generation and aggregation, and additional rounds of apoptosis, leading to cell death.
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