The inhalation anesthetic isoflurane induces a vicious cycle of apoptosis and amyloid beta-protein accumulation.
The anesthetic isoflurane has been reported to induce apoptosis and increase Abeta 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 (Abeta) 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 Abeta generation. We also tested the effects of inhibitors of Abeta aggregation (iAbeta5, 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 Abeta in the H4-APP cells. Isoflurane-induced Abeta generation could be blocked by the broad-based caspase inhibitor Z-VAD. The Abeta aggregation inhibitors, iAbeta5 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 Abeta generation in naive H4 cells. Finally, Abeta 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 Abeta secretion. Isoflurane also promotes Abeta aggregation. Accumulation of aggregated Abeta in the media can then promote apoptosis. The result is a vicious cycle of isoflurane-induced apoptosis, Abeta generation and aggregation, and additional rounds of apoptosis, leading to cell death.
Xie
Zhongcong
Z
Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Charlestown, Massachusetts 02129-2060, USA.
Dong
Yuanlin
Y
Maeda
Uta
U
Moir
Robert D
RD
Xia
Weiming
W
Culley
Deborah J
DJ
Crosby
Gregory
G
Tanzi
Rudolph E
RE
D000544:Alzheimer Disease / Q000139:chemically induced; D053829:Amyloid Precursor Protein Secretases / Q000187:drug effects / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D018685:Anesthetics, Inhalation / Q000009:adverse effects / Q000494:pharmacology / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D016282:Aspartic Acid Endopeptidases / Q000187:drug effects / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D007464:Clioquinol / Q000494:pharmacology; D003300:Copper; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D018303:Ganglioglioma / Q000473:pathology; D006801:Humans; D007530:Isoflurane / Q000009:adverse effects / Q000494:pharmacology / Q000633:toxicity*; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D015032:Zinc
D016229:Amyloid beta-Peptides; D018685:Anesthetics, Inhalation; D002614:Chelating Agents; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; C474023:iAbeta5 peptide; D003300:Copper; D007464:Clioquinol; D007530:Isoflurane; D053829:Amyloid Precursor Protein Secretases; D053148:Caspase 3; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human; D015032:Zinc