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Altered processing of amyloid precursor protein in the human neuroblastoma SH‐SY5Y by chronic hypoxia
Author(s) -
Webster Nicola J.,
Green Kim N.,
Peers Chris,
Vaughan Peter F. T.
Publication year - 2002
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2002.01236.x
Subject(s) - amyloid precursor protein , sh sy5y , neuroblastoma , endocrinology , hypoxia (environmental) , medicine , cytotoxic t cell , extracellular , muscarinic acetylcholine receptor , amyloid precursor protein secretase , microbiology and biotechnology , biology , receptor , chemistry , cell culture , alzheimer's disease , biochemistry , in vitro , oxygen , genetics , disease , organic chemistry
Alzheimer's disease (AD) is more prevalent following an ischemic or hypoxic episode, such as stroke. Indeed, brain levels of amyloid precursor protein (APP) and the cytotoxic amyloid β peptide (Aβ) fragment are enhanced in these patients and in animal models following experimental ischaemia. We have investigated the effect of chronic hypoxia (CH; 2.5% O 2 , 24 h) on processing of APP in the human neuroblastoma, SH‐SY5Y. We demonstrate that constitutive and muscarinic‐receptor‐enhanced secretion of the α‐secretase cleaved fragment of APP, sAPPα, was reduced by ∼60% in CH cells. The caspase inhibitor BOC‐D(Ome)FMK did not reverse this effect of CH, and CH cells were as viable as controls, based on MTT assays. Thus, loss of sAPPα is not related to cell death or caspase processing of APP. Pre‐incubation with antioxidants did not reverse the effect of CH, and the effect could not be mimicked by H 2 O 2 , discounting the involvement of reactive oxygen species in hypoxic loss of sAPPα. CH did not affect muscarinic activation of extracellular‐signal regulated kinase. However, expression of ADAM 10 (widely believed to be α‐secretase) was decreased approximately 50% following CH. Thus, CH selectively decreases processing of APP by the α‐secretase pathway, most likely by decreasing levels of ADAM 10.