NO Answer to Alzheimer's Disease?
Authors: Yi Chu, Donald D. Heistad
Journal: Circulation Research (2010)

W hat is the cause of Alzheimer's disease?What is the treatment?Currently, there is no (clear) answer.But wait, perhaps NO (nitric oxide) is part of the answer.2][3][4] In addition, cardiovascular risk factors and cerebrovascular dysfunction are associated with vascular dementia, as one might expect, but also with Alzheimer's disease. 5Thus, the current state of knowledge is that A␤ produces endothelial dysfunction, and endothelial dysfunction is associated with Alzheimer's disease.In this issue of Circulation Research, Austin et al 6 look at the association of endothelial dysfunction and Alzheimer's disease in a novel way.They tested the hypothesis that NO from endothelial nitric oxide synthase (eNOS) inhibits expression of amyloid precursor protein (APP) and processing of APP to A␤ in microvessels and brain parenchyma.They suggest that NO may directly modulate levels of A␤, APP, and the rate-limiting protease ␤-site APP cleaving enzyme (BACE)1, which, together with secretase-␥, cleaves APP to generate A␤. 7 The findings suggest that NO derived from normal endothelium protects against increases in A␤.An implication of the study is that decreased bioavailability of NO from endothelial dysfunction may contribute to increases in A␤ and possibly to Alzheimer's disease.First, the authors measured effects of changes in NO and cGMP on the pathway that produces amyloid plaques.They used 2 approaches to alter NO: enzymatic inhibition of NOS with N G -nitro-L-arginine methyl ester (L-NAME) and deletion of eNOS in mice.They also inhibited soluble guanylyl cyclase (sGC) with 1H-[1,2,4]oxadiazolo [4,3-a]quinoxalin-1one (ODQ) and increased cGMP with sildenafil.The major finding of the study is that inhibition of NO/sGC increased APP and A␤, whereas increases of cGMP reduced APP.The implication is that endothelial NO/sGC, and normal endothelial function, may suppress development of Alzheimer's disease.Second, Austin et al 6 measured expression and activity of secretase enzymes that cleave APP to generate the amyloi-dogenic A␤.They found that NO/cGMP modulates expression and activity of BACE1, but not other secretase enzymes.They also demonstrated that NO does not affect enzymes that degrade A␤.The findings localize effects of NO to synthesis, not degradation, of A␤.If the findings can be extrapolated to Alzheimer's disease, NO/sGC may be useful in prevention but not reversal of Alzheimer's disease.Third, the authors 6 demonstrated (by studying eNOS Ϫ/Ϫ mice) that NO derived from eNOS, not from neuronal NOS or inducible (i)NOS, accounts for effects that they observed.This approach was important because deletion of neuronal NOS may produce behavioral changes in mice 8,9 and because iNOS may modulate Alzheimer's disease-like changes. 10 -12 In this study, immunofluorescence indicated widespread expression of APP but restricted expression of BACE1.The findings support the rationale for current studies that target BACE1 for treatment of Alzheimer's disease. 7o severe neurological changes, let alone Alzheimer's disease, have been identified in eNOS-deficient mice. 13urthermore, the mice used in this study were young, before the age at which amyloid plaques and amyloid angiopathy would appear even in murine models of Alzheimer's disease. 14It would be of interest to determine whether eNOS modifies development of Alzheimer's disease, by crossing eNOS-deficient mice with Alzheimer's disease mice.Expression of eNOS has been examined in Alzheimer's disease with variable results. 15One might expect that eNOS deficiency would enhance the phenotype of Alzheimer's disease mice, because of increased APP, BACE1, and A␤ in both neurons and microvessels.Such studies have been reported with iNOS-deficient mice with conflicting results. 10 -12 This study 6 demonstrates a negative regulation of APP and BACE1 by eNOS/sGC at the protein level.Is regulation transcriptional, posttranscriptional, translational, or posttranslational?The promoter of BACE1 contains cAMP response element-binding (CREB) sites, 16 and phosphorylation (activation) of CREB protein is associated with downregulation of BACE1 expression in a mouse model of Alzheimer's disease. 17Because NO increases cGMP and activates cGMP protein kinase, which may then phosphorylate CREB, 18 NO may reduce BACE1 expression.The promoter of APP also contains AP-1 and Sp1 sites, which increase transcription of APP. 19NO increases AP-1 binding, but decreases Sp1 binding. 20We speculate that these effects of NO may modulate expression of BACE1 (and perhaps APP) at the transcription level and contribute to the findings by Austin et al. 6 Finally, this study points to the eNOS/NO/sGC/cGMP pathway as a possible therapeutic target for Alzheimer's disease.This potential target is consistent with the concept