Cognitive impairment in humanized APP×PS1 mice is linked to Aβ1–42 and NOX activation

Neurobiology of Disease

卷:44

Sunita Gupta¹  Daret St Clair²  Paulina R. Davis²  M. Paul Murphy³  Tina L. Beckett⁴  Annadora J. Bruce-Keller⁴  Alecia G. Knight⁴  Jessica M. McMullen⁵  Linda J. Van Eldik⁵  Jeffrey N. Keller⁵ 

[1] Corresponding author at: Inflammation and Neurodegeneration Laboratory, Pennington Biomedical Research Center/LSU, 6400 Perkins Road, Baton Rouge, LA 70808, USA. Fax: [phone].;

[2] Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY 40536, USA;

[3] Department of Toxicology, University of Kentucky College of Medicine, Lexington, KY 40536, USA;

[4] Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA;

[5] Sanders-Brown Center on Aging and Alzheimer's Disease Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA;

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

DOI  :  

来源: DOAJ

【 摘 要 】

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 Aβ1–42 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 Aβ1–42.

【 授权许可】

Unknown