title: Do proteomics analyses provide insights into reduced oxidative stress in the brain of an Alzheimer disease transgenic mouse model with an M631L amyloid precursor protein substitution and thereby the importance of amyloid-beta-resident methionine 35 in Alzheimer disease pathogenesis?
abstract: The single methionine (Met/M) residue of amyloid-beta (Aβ) peptide, at position 35 of the 42-mer, has important relevance for Aβ-induced oxidative stress and neurotoxicity. Recent in vivo brain studies in a transgenic (Tg) Alzheimer disease (AD) mouse model with Swedish and Indiana familial AD mutations in human amyloid precursor protein (APP) (referred to as the J20 Tg mouse) demonstrated increased levels of oxidative stress. However, the substitution of the Met631 residue of APP to leucine (Leu/L) (M631L in human APP numbering, referred to as M631L Tg and corresponding to residue 35 of Aβ1-42) resulted in no significant in vivo oxidative stress levels, thereby supporting the hypothesis that Met-35 of Aβ contributes to oxidative insult in the AD brain. It is conceivable that oxidative stress mediated by Met-35 of Aβ is important in regulating numerous downstream effects, leading to differential levels of relevant biochemical pathways in AD. Therefore, in the current study using proteomics, we tested the hypothesis that several brain proteins involved in pathways such as energy and metabolism, antioxidant activity, proteasome degradation, and pH regulation are altered in J20Tg versus M631L Tg AD mice.
authors.affiliation: Department of Chemistry, Center of Membrane Sciences, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: Rukhsana
authors.initials: R
authors.lastname: Sultana
authors.forename: Renã A S
authors.initials: RA
authors.lastname: Robinson
authors.forename: Miranda Bader
authors.initials: MB
authors.lastname: Lange
authors.forename: Ada
authors.initials: A
authors.lastname: Fiorini
authors.forename: Veronica
authors.initials: V
authors.lastname: Galvan
authors.forename: Joanna
authors.initials: J
authors.lastname: Fombonne
authors.forename: Austin
authors.initials: A
authors.lastname: Baker
authors.forename: Olivia
authors.initials: O
authors.lastname: Gorostiza
authors.forename: Junli
authors.initials: J
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Cai
authors.forename: William M
authors.initials: WM
authors.lastname: Pierce
authors.forename: Dale E
authors.initials: DE
authors.lastname: Bredesen
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D015180:Electrophoresis, Gel, Two-Dimensional; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D007930:Leucine / Q000235:genetics / Q000378:metabolism; D008715:Methionine / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D018384:Oxidative Stress / Q000235:genetics*; D011506:Proteins / Q000378:metabolism; D040901:Proteomics / Q000379:methods
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D011506:Proteins; D008715:Methionine; D007930:Leucine