Oxidised LDL-lipids increase beta amyloid production by SH-SY5Y cells through glutathione depletion and lipid raft formation

Irundika H.K. Dias, Jayna Mistry, Shaun Fell, Ana Reis, Corinne M. Spickett, Maria C Polidori, Greg Y.H. Lip, Helen R. Griffiths

Research output: Contribution to journalArticle

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. β-Amyloid (Aβ) peptide, which accumulates in Alzheimer disease (AD), arises from the initial cleavage of amyloid precursor protein by β-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 Aβ production by SH-SY5Y neuronal-like cells exposed to oxidized LDL (oxLDL). The viability of SH-SY5Y cells exposed to 4 μg oxLDL and 25 μM 27-hydroxycholesterol (27OH-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. 27OH-C and total lipids from LDL and oxLDL independently increased Aβ production by SH-SY5Y cells, and Aβ accumulation could be inhibited by desipramine and by N-acetylcysteine. These data suggest a mechanism whereby oxLDL lipids and 27OH-C can drive Aβ production by GSH depletion, ASMase-driven membrane remodeling, and BACE1 activation in neuronal cells. © 2014 The Authors.

LanguageEnglish
Pages48–59
Number of pages12
JournalFree Radical Biology and Medicine
Volume75
Early online date15 Jul 2014
DOIs
Publication statusPublished - Oct 2014

Fingerprint

Amyloid
Glutathione
Lipids
Sphingomyelin Phosphodiesterase
Amyloid Precursor Protein Secretases
Desipramine
LDL Lipoproteins
Acids
Dementia
Alzheimer Disease
Cholesterol
Lipoproteins
Glutathione Disulfide
Amyloid beta-Protein Precursor
Amyloid beta-Peptides
Acetylcysteine
Membrane Lipids
oxidized low density lipoprotein
Hypercholesterolemia
Lipid Metabolism

Bibliographical note

© 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

Funding: Dunhill Medical Trust (Grant R92/1108); COST CM1001 and COST BM1023 programs; Marie-Curie Intra-European Fellowship (FP7-PEOPLE-2009-IEF Project ID 255076“ATHERO_MASS”).

Supplementary data: http://dx.doi.org/10.1016/j.freeradbiomed.2014.07.012

Keywords

  • aging
  • BACE1
  • cholesterol
  • free radicals
  • GSH
  • lipid oxidation
  • lipid raft
  • low-density lipoprotein
  • OxLDL
  • Redox

Cite this

Dias, Irundika H.K. ; Mistry, Jayna ; Fell, Shaun ; Reis, Ana ; Spickett, Corinne M. ; Polidori, Maria C ; Lip, Greg Y.H. ; Griffiths, Helen R. / Oxidised LDL-lipids increase beta amyloid production by SH-SY5Y cells through glutathione depletion and lipid raft formation. In: Free Radical Biology and Medicine. 2014 ; Vol. 75. pp. 48–59.
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Oxidised LDL-lipids increase beta amyloid production by SH-SY5Y cells through glutathione depletion and lipid raft formation. / Dias, Irundika H.K.; Mistry, Jayna; Fell, Shaun; Reis, Ana; Spickett, Corinne M.; Polidori, Maria C; Lip, Greg Y.H.; Griffiths, Helen R.

In: Free Radical Biology and Medicine, Vol. 75, 10.2014, p. 48–59.

Research output: Contribution to journalArticle

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T1 - Oxidised LDL-lipids increase beta amyloid production by SH-SY5Y cells through glutathione depletion and lipid raft formation

AU - Dias, Irundika H.K.

AU - Mistry, Jayna

AU - Fell, Shaun

AU - Reis, Ana

AU - Spickett, Corinne M.

AU - Polidori, Maria C

AU - Lip, Greg Y.H.

AU - Griffiths, Helen R.

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KW - aging

KW - BACE1

KW - cholesterol

KW - free radicals

KW - GSH

KW - lipid oxidation

KW - lipid raft

KW - low-density lipoprotein

KW - OxLDL

KW - Redox

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