title: Cognitive impairment in humanized APP×PS1 mice is linked to Aβ(1-42) and NOX activation.
abstract: Cognitive impairment in Alzheimer's disease (AD) is strongly associated with both extensive deposition of amyloid β peptides and oxidative stress, but the exact role of these indices in the development of dementia is not clear. This study was designed to determine the relationship between cognitive impairment, activation of the free radical producing enzyme NADPH oxidase (NOX), and progressive changes in Aβ deposition and solubility in humanized APP×PS1 knock-in mice of increasing age. Data show that cognitive performance and expression of key synaptic proteins were progressively decreased in aging APP×PS1 mice. Likewise, NOX activity and expression of the specific NOX subunit NOX4 were significantly increased in APP×PS1 mice in an age-dependent manner, and NOX activity and cognitive impairment shared a significant linear relationship. Data further show that age-dependent increases in Aβ(1-42) had a significant linear relationship with both NOX activity and cognitive performance in APP×PS1 knock-in mice. Collectively, these data show that NOX expression and activity are significantly upregulated with age in this humanized model of Aβ pathogenesis, and suggest that NOX-associated redox pathways are intimately linked to both the loss of cognitive function and the deposition of Aβ(1-42).
authors.affiliation: Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA. annadora.bruce-keller@pbrc.edu
authors.forename: Annadora J
authors.initials: AJ
authors.lastname: Bruce-Keller
authors.forename: Sunita
authors.initials: S
authors.lastname: Gupta
authors.forename: Alecia G
authors.initials: AG
authors.lastname: Knight
authors.forename: Tina L
authors.initials: TL
authors.lastname: Beckett
authors.forename: Jessica M
authors.initials: JM
authors.lastname: McMullen
authors.forename: Paulina R
authors.initials: PR
authors.lastname: Davis
authors.forename: M Paul
authors.initials: MP
authors.lastname: Murphy
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Van Eldik
authors.forename: Daret
authors.initials: D
authors.lastname: St Clair
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Keller
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D000074288:Discs Large Homolog 1 Protein; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics*; D051528:Guanylate Kinases / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D019255:NADPH Oxidases / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics; D016704:Synapsins / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000074288:Discs Large Homolog 1 Protein; C000614189:Dlg1 protein, mouse; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D016704:Synapsins; D014404:Tubulin; C075222:amyloid beta-protein (1-42); D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D051528:Guanylate Kinases