Abstract 3063: Nitroglycerin Treatment Attenuates APP and BACE1 Protein Levels In Cerebral Microcirculation
Several cardiovascular risk factors are associated with an increased incidence of Alzheimer’s disease (AD); however, the mechanistic link is unknown. A common feature of cardiovascular risk factors is endothelial dysfunction, specifically, loss of bioavailability of endothelial nitric oxide (NO). Recently, we demonstrated that loss of endothelial NO led to increased protein levels of amyloid precursor protein (APP), β-site APP cleaving enzyme 1 (BACE1) and beta amyloid (Aβ) peptide. APP, the parent protein, when sequentially cleaved by BACE1 and γ-secretase generates amyloidogenic, Aβ, the primary component of AD plaques. Our data was the first to demonstrate a possible mechanism linking endothelial dysfunction, via loss of endothelial NO, with the upregulation of important AD related proteins in the cerebral microvasculature. Therefore, we sought to determine if supplementation of cultured human brain microvascular endothelial cells with NO, by utilizing the NO donor, DETA NONOate, would attenuate APP and BACE1 protein. DETA NONOate, 10-8 to 10-6 M, reduced expression of APP and BACE1 as compared to untreated control cells (n=3). To test the effects of NO supplementation in vivo, we treated endothelial nitric oxide synthase deficient (eNOS-/-) mice with 30 mg/kg nitroglycerine b.i.d. or vehicle via subcutaneous injections for 3 days. No difference was observed in blood pressure between animals treated with vehicle (n=7) or nitroglycerine (n=6) (P>0.05) or before and after nitroglycerine treatment (n=6, P>0.05). As expected, cerebral microvessles of eNOS-/- animals treated with nitroglycerine displayed increased levels of cGMP as compared to vehicle (n=7-8; P<0.05). Moreover, APP and BACE1 protein levels were statistically lower in cerebral microvessels from eNOS-/- mice treated with nitroglycerine as compared to vehicle treated (n=6-7, APP, P<0.05; BACE1, P<0.05). These data indicate that supplementation with NO is able to suppress APP and BACE1 levels in the cerebrovascular endothelium. Our findings suggest that preservation of NO/cGMP signaling may be an important therapeutic target in preventing and treating mild cognitive impairment as well as AD.
- © 2012 by American Heart Association, Inc.