The exact etiology of sporadic AD is unclear but it is interesting that several cardiovascular risk factors are associated with higher incidence of AD. The link between these risk factors and AD has yet to be identified; however, a common feature is endothelial dysfunction, specifically, decreased bioavailability of nitric oxide (NO).
To determine the relationship between endothelial derived NO and the expression and processing of amyloid precursor protein (APP).
Methods and Results
We utilized human brain microvascular endothelial cells (BMECs) to examine the role of NO in modulating APP expression and processing in vitro. Inhibition of endothelial nitric oxide synthase (eNOS) with the specific NOS inhibitor, N(G)-Nitro-L-Arginine Methyl Ester (L-NAME), led to increased APP and β-site APP cleaving enzyme 1 (BACE1) protein levels as well as increased secretion of the amyloidogenic, amyloid beta (Aβ), peptide (control 10.93 ± 0.70 pg/mL; L-NAME 168.21 ± 27.38 pg/mL, P<0.001). To examine the role of NO in modulation of APP expression and processing in vivo, we utilized brain and cerebral microvessels from the eNOS−/− mice. Brain tissue from eNOS deficient (eNOS−/−) mice had statistically higher APP and BACE1 protein levels as well as increased BACE1 enzyme activity and Aβ (Aβ1–42 wild-type control 0.737pg/mg; eNOS−/− 1.475pg/mg, P<0.05), compared to wild-type controls (n=6–8 animals per background). Brain microvessels from eNOS−/− mice also showed statistically higher BACE1 protein levels as compared to wild-type control.
Our data suggest that endothelial NO plays an important role in modulating APP expression and processing within the brain and cerebrovasculature. The NO/cGMP pathway may be an important therapeutic target in preventing and treating mild cognitive impairment as well as AD.
Keywords: Endothelium, Amyloid precursor protein, Alzheimer’s disease, cerebrovascular biology, beta amyloid