title: Antisense directed against PS-1 gene decreases brain oxidative markers in aged senescence accelerated mice (SAMP8) and reverses learning and memory impairment: a proteomics study.
abstract: Amyloid β-peptide (Aβ) plays a central role in the pathophysiology of Alzheimer's disease (AD) through the induction of oxidative stress. This peptide is produced by proteolytic cleavage of amyloid precursor protein (APP) by the action of β- and γ-secretases. Previous studies demonstrated that reduction of Aβ, using an antisense oligonucleotide (AO) directed against the Aβ region of APP, reduced oxidative stress-mediated damage and prevented or reverted cognitive deficits in senescence-accelerated prone mice (SAMP8), a useful animal model for investigating the events related to Aβ pathology and possibly to the early phase of AD. In the current study, aged SAMP8 were treated by AO directed against PS-1, a component of the γ-secretase complex, and tested for learning and memory in T-maze foot shock avoidance and novel object recognition. Brain tissue was collected to identify the decrease of oxidative stress and to evaluate the proteins that are differently expressed and oxidized after the reduction in free radical levels induced by Aβ. We used both expression proteomics and redox proteomics approaches. In brain of AO-treated mice a decrease of oxidative stress markers was found, and the proteins identified by proteomics as expressed differently or nitrated are involved in processes known to be impaired in AD. Our results suggest that the treatment with AO directed against PS-1 in old SAMP8 mice reverses learning and memory deficits and reduces Aβ-mediated oxidative stress with restoration to the normal condition and identifies possible pharmacological targets to combat this devastating dementing disease.
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy; Department of Chemistry, Center of Membrane Sciences, Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: Ada
authors.initials: A
authors.lastname: Fiorini
authors.affiliation: Department of Chemistry, Center of Membrane Sciences, Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: Rukhsana
authors.initials: R
authors.lastname: Sultana
authors.affiliation: Department of Chemistry, Center of Membrane Sciences, Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40506, USA; Department of Biochemistry, Institute of Animal Sciences, University of Bonn, Bonn, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Förster
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Perluigi
authors.affiliation: Department of Chemistry, Center of Membrane Sciences, Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Cenini
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cini
authors.affiliation: Department of Nephrology and Proteomics Center, University of Louisville, Louisville, KY 40292, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Cai
authors.affiliation: Department of Nephrology and Proteomics Center, University of Louisville, Louisville, KY 40292, USA.
authors.forename: Jon B
authors.initials: JB
authors.lastname: Klein
authors.affiliation: Division of Geriatric Medicine Saint Louis University School of Medicine, St. Louis, MO, USA; VA Medical Center, St. Louis, MO, USA.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Farr
authors.affiliation: Division of Geriatric Medicine Saint Louis University School of Medicine, St. Louis, MO, USA; VA Medical Center, St. Louis, MO, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Niehoff
authors.affiliation: Division of Geriatric Medicine Saint Louis University School of Medicine, St. Louis, MO, USA; VA Medical Center, St. Louis, MO, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Morley
authors.affiliation: Division of Geriatric Medicine Saint Louis University School of Medicine, St. Louis, MO, USA; VA Medical Center, St. Louis, MO, USA.
authors.forename: Vijaya B
authors.initials: VB
authors.lastname: Kumar
authors.affiliation: Department of Chemistry, Center of Membrane Sciences, Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40506, USA. Electronic address: dabcns@uky.edu.
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D015180:Electrophoresis, Gel, Two-Dimensional; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D018782:Maze Learning / Q000187:drug effects*; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D053764:Presenilin-1 / Q000037:antagonists & inhibitors*; D040901:Proteomics
chemical_list: D016376:Oligonucleotides, Antisense; D053764:Presenilin-1; C580804:presenilin 1, mouse
keywords: 5-bromo-4-chloro-3-indolyl phosphate/nitrotetrazolium blue chloride; AATC; AD; AO; APP; Alzheimer's disease; Amyloid precursor protein; Amyloid β-peptide; Aβ; BCIP/NBT; CRMP-1; CRMP-2; ES1; ES1 protein homolog; FAD; IDH3A, isocitrate dehydrogenase subunit alpha; L-lactate dehydrogenase; LDH; M1/M2 KPYM; MCI; NAD; NFT; NSF; PDHA1 and PDH; PS-1; PS-2; SAM; SNAPs; Senescence accelerated mouse; TPI; V-ATPase; amyloid precursor protein; amyloid β-peptide; antisense oligonucleotide; aspartate aminotransferase; dihydropyrimidinase-related protein 1; dihydropyrimidinase-related protein 2; familial Alzheimer's disease; intracellular neurofibrillary tangles; isocitrate dehydrogenase; isoform M1 pyruvate kinase isozymes; mild cognitive impairment; presenilin-1; presenilin-2; pyruvate dehydrogenase E1 component subunit alpha and beta; senescence accelerated mouse; soluble N-ethylmaleimide-sensitive factor attachment proteins; triosephosphate isomerase; vacuolar-type H+-ATPase; vesicle-fusing ATPase/vesicular-fusion protein NSF