Universität zu Köln

Dias, Irundika H. K., Mistry, Jayna, Fell, Shaun, Reis, Ana ORCID: 0000-0002-4537-9902, Spickett, Corinne M., Polidori, Maria C., Lip, Gregory Y. H. and Griffiths, Helen R. (2014). Oxidized LDL lipids increase beta-amyloid production by SH-SY5Y cells through glutathione depletion and lipid raft formation. Free Radic. Biol. Med., 75. S. 48 - 60. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1873-4596

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Abstract

Elevated total cholesterol in midlife has been associated with increased risk of dementia in later life. We have previously shown that low-density lipoprotein (LDL) is more oxidized in the plasma of dementia patients, although total cholesterol levels are not different from those of age-matched controls. beta-Amyloid (A beta) peptide, which accumulates in Alzheimer disease (AD), arises from the initial cleavage of amyloid precursor protein by beta-secretase-1 (BACE1). BACE1 activity is regulated by membrane lipids and raft formation. Given the evidence for altered lipid metabolism in AD, we have investigated a mechanism for enhanced A beta production by SH-SY5Y neuronal-like cells exposed to oxidized LDL (oxLDL). The viability of SH-SY5Y cells exposed to 4 mu g oxLDL and 25 mu M 27-hydroxycholesterol (270H-C) was decreased significantly. Lipids, but not proteins, extracted from oxLDL were more cytotoxic than oxLDL. In parallel, the ratio of reduced glutathione (GSH) to oxidized glutathione was decreased at sublethal concentrations of lipids extracted from native and oxLDL. GSH loss was associated with an increase in acid sphingomyelinase (ASMase) activity and lipid raft formation, which could be inhibited by the ASMase inhibitor desipramine. 270H-C and total lipids from LDL and oxLDL independently increased A beta production by SH-SY5Y cells, and A beta accumulation could be inhibited by desipramine and by N-acetylcysteine. These data suggest a mechanism whereby oxLDL lipids and 270H-C can drive A beta production by GSH depletion, ASMase-driven membrane remodeling, and BACE1 activation in neuronal cells. (C) 2014 The Authors. Published by Elsevier Inc.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Dias, Irundika H. K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mistry, Jayna UNSPECIFIED UNSPECIFIED UNSPECIFIED Fell, Shaun UNSPECIFIED UNSPECIFIED UNSPECIFIED Reis, Ana UNSPECIFIED orcid.org/0000-0002-4537-9902 UNSPECIFIED Spickett, Corinne M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Polidori, Maria C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lip, Gregory Y. H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Griffiths, Helen R. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-428002
DOI:	10.1016/j.freeradbiomed.2014.07.012
Journal or Publication Title:	Free Radic. Biol. Med.
Volume:	75
Page Range:	S. 48 - 60
Date:	2014
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	1873-4596
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ACID SPHINGOMYELINASE; OXIDATIVE STRESS; COMMON VARIANTS; CHOLESTEROL; 27-HYDROXYCHOLESTEROL; INHIBITION; 24-HYDROXYCHOLESTEROL; ACCUMULATION; INVOLVEMENT; ASSOCIATION Multiple languages Biochemistry & Molecular Biology; Endocrinology & Metabolism Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/42800