Endothelial nitric oxide modulates expression and processing of amyloid precursor protein.
BACKGROUND
the exact etiology of sporadic Alzheimer disease (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).


OBJECTIVE
to determine the relationship between endothelial derived NO and the expression and processing of amyloid precursor protein (APP).


RESULTS
we used human brain microvascular endothelial cells 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 L-NAME (N(G)-nitro-l-arginine methyl ester) led to increased APP and BACE1 (β-site APP-cleaving enzyme1) protein levels, as well as increased secretion of the amyloidogenic peptide amyloid β (Aβ) (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 used brain and cerebral microvessels from eNOS-deficient (eNOS(-/-)) mice. Brain tissue from eNOS(-/-) mice had statistically higher APP and BACE1 protein levels, as well as increased BACE1 enzyme activity and Aβ (Aβ(1)(-)(42) wild-type control, 0.737 pg/mg; eNOS(-/-), 1.475 pg/mg; P<0.05), compared with wild-type controls (n=6 to 8 animals per background). Brain microvessels from eNOS(-/-) mice also showed statistically higher BACE1 protein levels as compared with wild-type control.


CONCLUSIONS
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.
Departments of Anesthesiology and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minn., 55905, USA.
Susan A
SA
Austin
Anantha V
AV
Santhanam
Zvonimir S
ZS
Katusic
D000544:Alzheimer Disease; D053829:Amyloid Precursor Protein Secretases / Q000032:analysis; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000032:analysis; D001921:Brain / Q000098:blood supply / Q000166:cytology / Q000378:metabolism*; D001923:Brain Chemistry; D002560:Cerebrovascular Circulation; D006152:Cyclic GMP; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008833:Microcirculation; D009569:Nitric Oxide / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000502:physiology*
C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; D006152:Cyclic GMP