Loss of Endothelial Nitric Oxide Synthase Promotes p25 Generation and Tau Phosphorylation in a Murine Model of Alzheimer's Disease

Susan A. Austin, Zvonimir S. Katusic

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Rationale: Alzheimer's disease has an unknown pathogenesis; however, cardiovascular risk factors are associated with a higher incidence of Alzheimer's disease. A defining feature of endothelial dysfunction induced by cardiovascular risk factors is reduced bioavailable endothelial nitric oxide (NO). We previously demonstrated that endothelial NO acts as an important signaling molecule in neuronal tissue. Objective: We sought to determine the relationship between the loss of endothelial NO synthase (eNOS) and tau phosphorylation in neuronal tissue. Methods and Results: We used eNOS knockout (-/-) mice as well as an Alzheimer's disease mouse model, amyloid precursor protein (APP)/PSEN1dE9 +/- (PS1) that lacked eNOS (APP/PS1/eNOS -/-) to examine expression of tau kinases and tau phosphorylation. Brain tissue from eNOS -/- mice had statistically higher ratios of p25/p35, indicative of increased cyclin-dependent kinase 5 activity as compared with wild-type (n=8, P<0.05). However, tau phosphorylation was unchanged in eNOS -/- mice (P>0.05). Next, we determined the role of NO in tau pathology in APP/PS1/eNOS -/-. These mice had significantly higher levels of p25, a higher p25/p35 ratio (n=12-14; P<0.05), and significantly higher cyclin-dependent kinase 5 activity (n=4; P<0.001). Importantly, APP/PS1/eNOS -/- mice also had significantly increased tau phosphorylation (n=4-6; P<0.05). No other changes in amyloid pathology, antioxidant pathways, or neuroinflammation were observed in APP/PS1/eNOS -/- mice as compared with APP/PS1 mice. Conclusions: Our data suggests that loss of endothelial NO plays an important role in the generation of p25 and resulting tau phosphorylation in neuronal tissue. These findings provide important new insights into the molecular mechanisms linking endothelial dysfunction with the pathogenesis of Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)1128-1134
Number of pages7
JournalCirculation research
Issue number10
StatePublished - Oct 28 2016


  • Alzheimer's disease
  • Cdk5
  • cerebrovascular disease
  • endothelial nitric oxide synthase
  • tau

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


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