title: Oxidative modification of lipoic acid by HNE in Alzheimer disease brain.
abstract: Alzheimer disease (AD) is an age-related neurodegenerative disease characterized by the presence of three pathological hallmarks: synapse loss, extracellular senile plaques (SP) and intracellular neurofibrillary tangles (NFTs). The major component of SP is amyloid β-peptide (Aβ), which has been shown to induce oxidative stress. The AD brain shows increased levels of lipid peroxidation products, including 4-hydroxy-2-nonenal (HNE). HNE can react covalently with Cys, His, or Lys residues on proteins, altering structure and function of the latter. In the present study we measured the levels of the HNE-modified lipoic acid in brain of subjects with AD and age-matched controls. Lipoic acid is a key co-factor for a number of proteins including pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, key complexes for cellular energetics. We observed a significant decrease in the levels of HNE-lipoic acid in the AD brain compared to that of age-matched controls. To investigate this phenomenon further, the levels and activity of lipoamide dehydrogenase (LADH) were measured in AD and control brains. Additionally, LADH activities were measured after in-vitro HNE-treatment to mice brains. Both LADH levels and activities were found to be significantly reduced in AD brain compared to age-matched control. HNE-treatment also reduced the LADH activity in mice brain. These data are consistent with a two-hit hypothesis of AD: oxidative stress leads to lipid peroxidation that, in turn, causes oxidative dysfunction of key energy-related complexes in mitochondria, triggering neurodegeneration. This study is consonant with the notion that lipoic acid supplementation could be a potential treatment for the observed loss of cellular energetics in AD and potentiate the antioxidant defense system to prevent or delay the oxidative stress in and progression of this devastating dementing disorder.
authors.affiliation: Department of Chemistry, University of Kentucky, Lexington, KY 40506-0055, USA ; Center for Membrane Sciences, University of Kentucky, Lexington, KY 40506-0055, USA ; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA.
authors.forename: Sarita S
authors.initials: SS
authors.lastname: Hardas
authors.forename: Rukhsana
authors.initials: R
authors.lastname: Sultana
authors.forename: Amy M
authors.initials: AM
authors.lastname: Clark
authors.forename: Tina L
authors.initials: TL
authors.lastname: Beckett
authors.forename: Luke I
authors.initials: LI
authors.lastname: Szweda
authors.forename: M Paul
authors.initials: MP
authors.lastname: Murphy
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
mesh_terms: D000447:Aldehydes / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D008058:Dihydrolipoamide Dehydrogenase / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D008063:Thioctic Acid / Q000378:metabolism*
chemical_list: D000447:Aldehydes; D008063:Thioctic Acid; D008058:Dihydrolipoamide Dehydrogenase; C027576:4-hydroxy-2-nonenal
keywords: 4-hydroxy-2-trans nonenal (HNE); AD, Alzheimer disease; Alzheimer disease; HNE, 4-hydroxy-2-trans nonenal; HNE-LA, HNE-bound lipoic acid; IPL, inferior parietal lobule; LA, lipoic acid; LADH, lipoamide dehydrogenase/dihydrolipoamide dehydrogenase; Lipid peroxidation; Lipoamide dehydrogenase; Lipoic acid
references.citation: J Am Geriatr Soc. 1998 Dec;46(12):1566-72
references.pmid: 9848820
references.citation: Free Radic Biol Med. 2007 Feb 1;42(3):371-84
references.pmid: 17210450
references.citation: Eur J Pharmacol. 2004 Apr 19;490(1-3):115-25
references.pmid: 15094078
references.citation: Free Radic Biol Med. 2002 Jul 15;33(2):182-91
references.pmid: 12106814
references.citation: J Neurochem. 2001 Jul;78(2):413-6
references.pmid: 11461977
references.citation: Neurobiol Aging. 2002 Sep-Oct;23(5):655-64
references.pmid: 12392766
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2004 Nov 15;131B(1):60-6
references.pmid: 15389771
references.citation: J Neurochem. 1997 Jan;68(1):255-64
references.pmid: 8978733
references.citation: Ann N Y Acad Sci. 1989;573:254-66
references.pmid: 2634348
references.citation: Neurology. 2005 Apr 12;64(7):1152-6
references.pmid: 15824339
references.citation: Neurobiol Dis. 1998 Oct;5(4):229-43
references.pmid: 9848093
references.citation: Eur J Biochem. 1986 Feb 17;155(1):103-9
references.pmid: 3948874
references.citation: Neurobiol Dis. 2006 May;22(2):223-32
references.pmid: 16466929
references.citation: Acta Neuropathol. 2009 Jul;118(1):5-36
references.pmid: 19381658
references.citation: Free Radic Biol Med. 2001 May 1;30(9):992-9
references.pmid: 11316579
references.citation: Neurodegeneration. 1996 Dec;5(4):473-6
references.pmid: 9117565
references.citation: Gerontology. 1994;40(5):246-52
references.pmid: 7959080
references.citation: Acta Neuropathol. 2008 Sep;116(3):261-8
references.pmid: 18629521
references.citation: Life Sci. 2001 May 4;68(24):2741-50
references.pmid: 11400916
references.citation: Free Radic Biol Med. 2009 Sep 1;47(5):469-84
references.pmid: 19500666
references.citation: Toxicology. 2004 Nov 15;204(2-3):209-18
references.pmid: 15388247
references.citation: Neurochem Int. 2000 Feb;36(2):97-112
references.pmid: 10676873
references.citation: Mitochondrion. 2007 Sep;7(5):297-310
references.pmid: 17625988
references.citation: Ann Neurol. 1996 May;39(5):592-8
references.pmid: 8619544
references.citation: Ann Neurol. 1995 Sep;38(3):357-66
references.pmid: 7668820
references.citation: Mass Spectrom Rev. 2004 Jul-Aug;23(4):281-305
references.pmid: 15133838
references.citation: Biochem Pharmacol. 1992 Oct 20;44(8):1637-49
references.pmid: 1417985
references.citation: Trends Mol Med. 2001 Dec;7(12):548-54
references.pmid: 11733217
references.citation: Mech Ageing Dev. 2001 Dec;123(1):39-46
references.pmid: 11640950
references.citation: Neurochem Res. 2008 Dec;33(12):2540-6
references.pmid: 18320305
references.citation: J Cell Mol Med. 2005 Jul-Sep;9(3):531-41
references.pmid: 16202202
references.citation: Chem Res Toxicol. 1997 May;10(5):495-506
references.pmid: 9168246
references.citation: Free Radic Biol Med. 1997;23(1):134-47
references.pmid: 9165306
references.citation: J Neurochem. 2004 Mar;88(6):1352-60
references.pmid: 15009635
references.citation: J Alzheimers Dis. 2000 Jun;2(2):123-131
references.pmid: 12214102
references.citation: Biochim Biophys Acta. 2007 Apr;1772(4):494-502
references.pmid: 17142016
references.citation: Neuromolecular Med. 2004;5(2):147-62
references.pmid: 15075441
references.citation: Neurotox Res. 2003;5(7):515-20
references.pmid: 14715435
references.citation: Biochim Biophys Acta. 2000 Jul 26;1502(1):139-44
references.pmid: 10899439
references.citation: Ann N Y Acad Sci. 2008 Dec;1147:180-95
references.pmid: 19076441
references.citation: Antioxid Redox Signal. 2012 Dec 1;17(11):1610-55
references.pmid: 22115501
references.citation: J Neurochem. 1995 Nov;65(5):2146-56
references.pmid: 7595501
references.citation: Neurobiol Aging. 1997 Sep-Oct;18(5):457-61
references.pmid: 9390770
references.citation: Expert Opin Investig Drugs. 2007 Dec;16(12):1921-31
references.pmid: 18042001
references.citation: Biochem Pharmacol. 1996 Feb 9;51(3):233-8
references.pmid: 8573188
references.citation: J Bioenerg Biomembr. 2005 Aug;37(4):207-25
references.pmid: 16167177
references.citation: Lancet Neurol. 2004 Apr;3(4):219-26
references.pmid: 15039034
references.citation: Ann Neurol. 1994 Mar;35(3):312-8
references.pmid: 8122883
references.citation: Toxicology. 1997 Sep 26;122(1-2):111-22
references.pmid: 9274807
references.citation: Biochem J. 1985 Apr 15;227(2):629-38
references.pmid: 4004782
references.citation: Neurobiol Aging. 2006 Feb;27(2):262-9
references.pmid: 16399211
references.citation: J Bioenerg Biomembr. 2009 Oct;41(5):441-6
references.pmid: 19777328
references.citation: Eur J Nucl Med Mol Imaging. 2005 Apr;32(4):486-510
references.pmid: 15747152
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14670-5
references.pmid: 19667196
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19318-23
references.pmid: 19050078
references.citation: Neurobiol Aging. 2008 Jan;29(1):51-70
references.pmid: 17055614
references.citation: Chem Res Toxicol. 2005 Aug;18(8):1324-31
references.pmid: 16097806
references.citation: Physiol Rev. 1997 Oct;77(4):1081-132
references.pmid: 9354812
references.citation: Biochim Biophys Acta. 2002 Mar 16;1586(2):177-89
references.pmid: 11959459
references.citation: Biochemistry. 1998 Nov 10;37(45):15835-41
references.pmid: 9843389
references.citation: IUBMB Life. 2000 Oct-Nov;50(4-5):315-21
references.pmid: 11327326
references.citation: Neurobiol Aging. 1998 Jan-Feb;19(1):33-6
references.pmid: 9562500
references.citation: J Biol Chem. 1986 May 5;261(13):6084-9
references.pmid: 3084478
references.citation: Ann Neurol. 2005 Oct;58(4):623-6
references.pmid: 16037976
references.citation: Ann N Y Acad Sci. 2008 Dec;1147:70-8
references.pmid: 19076432
references.citation: J Alzheimers Dis. 2007 Sep;12(2):195-206
references.pmid: 17917164
references.citation: J Alzheimers Dis. 2009;16(4):763-74
references.pmid: 19387111
references.citation: Neuroscience. 2007 Jul 13;147(3):674-9
references.pmid: 17570602
references.citation: Antioxid Redox Signal. 2012 Dec 1;17(11):1580-9
references.pmid: 22352679
references.citation: J Neurochem. 1997 Sep;69(3):1161-9
references.pmid: 9282939
references.citation: J Alzheimers Dis. 2011;24(1):77-84
references.pmid: 21383494