title: Antisense directed at the Abeta region of APP decreases brain oxidative markers in aged senescence accelerated mice.
abstract: Amyloid beta-peptide (Abeta) is known to induce free radical-mediated oxidative stress in the brain. Free radical-mediated damage to the neuronal membrane components has been implicated in the etiology of Alzheimer's disease (AD). Abeta is produced by proteolytic processing of the amyloid precursor protein (APP). The senescence accelerated mouse prone 8 (SAMP8) strain was developed by phenotypic selection from a common genetic pool. The SAMP8 strain exhibits age-related deterioration in memory and learning as well as Abeta accumulation, and it is considered an effective model for studying brain aging in accelerated senescence. Previous research has shown that a phosphorothiolated antisense oligonucleotide directed against the Abeta region of APP decreases the expression of APP and reverses deficits in learning and memory in aged SAMP8 mice. Consistent with other reports, our previous study showed that 12-month-old SAMP8 mice have increased levels of oxidative stress markers in the brain compared with that in brains from 4-month-old SAMP8 mice. In the current study, 12-month-old SAMP8 mice were treated with antisense oligonucleotide directed against the Abeta region of APP, and the oxidative markers in brain were decreased significantly. Therefore, we conclude that Abeta may contribute to the oxidative stress found in aged SAMP8 mice that have learning and memory impairments. These results are discussed in reference to AD.
authors.affiliation: Department of Chemistry, Center of Membrane Sciences, University of Kentucky, Lexington 40506-0055, USA.
authors.forename: H Fai
authors.initials: HF
authors.lastname: Poon
authors.forename: Gururaj
authors.initials: G
authors.lastname: Joshi
authors.forename: Rukhsana
authors.initials: R
authors.lastname: Sultana
authors.forename: Susan A
authors.initials: SA
authors.lastname: Farr
authors.forename: William A
authors.initials: WA
authors.lastname: Banks
authors.forename: John E
authors.initials: JE
authors.lastname: Morley
authors.forename: Vittorio
authors.initials: V
authors.lastname: Calabrese
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000447:Aldehydes / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000235:genetics; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008815:Mice, Inbred Strains; D009474:Neurons / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D000447:Aldehydes; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; D016376:Oligonucleotides, Antisense; D017392:Thiobarbituric Acid Reactive Substances; C002744:3-nitrotyrosine; D014443:Tyrosine; D005974:Glutamate-Ammonia Ligase; C027576:4-hydroxy-2-nonenal