Loss of Endothelial Nitric Oxide Synthase Promotes p25 Generation and Tau Phosphorylation in a Murine Model of Alzheimer's Disease
Rationale: Alzheimer's disease (AD) has an unknown etiology; however, cardiovascular risk factors are associated with a higher incidence of AD. A defining feature of endothelial dysfunction induced by cardiovascular risk factors is reduced bioavailable endothelial nitric oxide (NO). We previously demonstrated endothelial NO acts as an important signaling molecule in neuronal tissue.
Objective: We sought to determine the relationship between the loss of endothelial nitric oxide synthase (eNOS) and tau phosphorylation in neuronal tissue.
Methods and Results: We utilized eNOS knockout (-/-) mice as well as an AD mouse model, APP/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 (Cdk5) activity as compared to 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 Cdk5 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 to 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 AD.
- Received August 1, 2016.
- Revision received August 26, 2016.
- Accepted September 6, 2016.