title: Oxidized LDL lipids increase β-amyloid production by SH-SY5Y cells through glutathione depletion and lipid raft formation.
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 4μg oxLDL and 25µM 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.
authors.affiliation: Life and Health Sciences and Aston Research Centre for Healthy Ageing, Aston University, Birmingham, West Midlands B4 7ET, UK.
authors.forename: Irundika H K
authors.initials: IH
authors.lastname: Dias
authors.affiliation: Life and Health Sciences and Aston Research Centre for Healthy Ageing, Aston University, Birmingham, West Midlands B4 7ET, UK.
authors.forename: Jayna
authors.initials: J
authors.lastname: Mistry
authors.affiliation: Life and Health Sciences and Aston Research Centre for Healthy Ageing, Aston University, Birmingham, West Midlands B4 7ET, UK.
authors.forename: Shaun
authors.initials: S
authors.lastname: Fell
authors.affiliation: Life and Health Sciences and Aston Research Centre for Healthy Ageing, Aston University, Birmingham, West Midlands B4 7ET, UK.
authors.forename: Ana
authors.initials: A
authors.lastname: Reis
authors.affiliation: Life and Health Sciences and Aston Research Centre for Healthy Ageing, Aston University, Birmingham, West Midlands B4 7ET, UK.
authors.forename: Corinne M
authors.initials: CM
authors.lastname: Spickett
authors.affiliation: Institute of Geriatrics, University of Cologne, Cologne, Germany.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Polidori
authors.affiliation: Centre for Cardiovascular Sciences, City Hospital Birmingham, Birmingham B18 7QH, UK.
authors.forename: Gregory Y H
authors.initials: GY
authors.lastname: Lip
authors.affiliation: Life and Health Sciences and Aston Research Centre for Healthy Ageing, Aston University, Birmingham, West Midlands B4 7ET, UK. Electronic address: helen.griffiths@aston.ac.uk.
authors.forename: Helen R
authors.initials: HR
authors.lastname: Griffiths
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D008078:Cholesterol, LDL / Q000378:metabolism*; D003891:Desipramine / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism*; D019803:Glutathione Disulfide / Q000737:chemistry; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D050356:Lipid Metabolism; D008077:Lipoproteins, LDL / Q000097:blood / Q000494:pharmacology*; D021962:Membrane Microdomains / Q000378:metabolism*; D010084:Oxidation-Reduction; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: D016229:Amyloid beta-Peptides; D008078:Cholesterol, LDL; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D006888:Hydroxycholesterols; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; C076996:27-hydroxycholesterol; D013108:Sphingomyelin Phosphodiesterase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D005978:Glutathione; D003891:Desipramine; D019803:Glutathione Disulfide; D000111:Acetylcysteine
keywords: Aging; BACE1; Cholesterol; Free radicals; GSH; Lipid oxidation; Lipid raft; Low-density lipoprotein; OxLDL; Redox