Cognitive impairment in humanized APP x PS1 mice is linked to Aβ1-42 and NOX activation

NEUROBIOLOGY OF DISEASE

卷:44

Article

Bruce-Keller, Annadora J.¹  Beckett, Tina L.^2,3  McMullen, Jessica M.⁴  Davis, Paulina R.^2,3  Murphy, M. Paul^2,3  Van Eldik, Linda J.^2,5  St Clair, Daret⁴ 

[1] Louisiana State Univ, Pennington Biomed Res Ctr, Inflammat & Neurodegenerat Lab, Baton Rouge, LA 70808 USA

[2] Univ Kentucky, Sanders Brown Ctr Aging & Alzheimers Dis Ctr, Coll Med, Lexington, KY 40536 USA

[3] Univ Kentucky, Dept Mol & Cellular Biochem, Coll Med, Lexington, KY 40536 USA

[4] Univ Kentucky, Dept Toxicol, Coll Med, Lexington, KY 40536 USA

[5] Univ Kentucky, Dept Anat & Neurobiol, Coll Med, Lexington, KY 40536 USA

关键词: Aging;    Dementia;    Oxidative stress;    Redox signaling pathways;    Synapse loss;   

DOI  :  10.1016/j.nbd.2011.07.012

来源: Elsevier

【 摘 要 】

Cognitive impairment in Alzheimer's disease (AD) is strongly associated with both extensive deposition of amyloid beta 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 A beta deposition and solubility in humanized APP x PS1 knock-in mice of increasing age. Data show that cognitive performance and expression of key synaptic proteins were progressively decreased in aging APP x PS1 mice. Likewise, NOX activity and expression of the specific NOX subunit NOX4 were significantly increased in APP x 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 A beta(1-42) had a significant linear relationship with both NOX activity and cognitive performance in APP x PS1 knock-in mice. Collectively, these data show that NOX expression and activity are significantly upregulated with age in this humanized model of A beta pathogenesis, and suggest that NOX-associated redox pathways are intimately linked to both the loss of cognitive function and the deposition of A beta(1-42). (C) 2011 Elsevier Inc. All rights reserved.

【 授权许可】

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