Cognitive impairment in humanized APP×PS1 mice is linked to Aβ 1-42 and NOX activation

Annadora J. Bruce-Keller, Sunita Gupta, Alecia G. Knight, Tina L. Beckett, Jessica M. McMullen, Paulina R. Davis, M. Paul Murphy, Linda J. Van Eldik, Daret St Clair, Jeffrey N. Keller

Research output: Contribution to journalArticlepeer-review

73 Scopus citations


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.

Original languageEnglish
Pages (from-to)317-326
Number of pages10
JournalNeurobiology of Disease
Issue number3
StatePublished - Dec 2011

Bibliographical note

Funding Information:
The authors are grateful to Dr. Barry Robert and Cynthia Kloster for exemplary veterinary assistance. Additional gratitude goes to Teresa Noel for expert training and leadership in animal husbandry and colony management. This work was supported by grants from the NIH ( NS46267 and AG05119 ), and also used PBRC Core facilities (Animal Phenotyping) that are funded by the NIH ( P20-RR021945 and P30-DK072476 ).


  • Aging
  • Dementia
  • Oxidative stress
  • Redox signaling pathways
  • Synapse loss

ASJC Scopus subject areas

  • Neurology


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