Endothelial Nitric Oxide Modulates Expression and Processing of Amyloid Precursor Protein

Abstract

Rationale: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). Key Words: endothelium Ⅲ amyloid precursor protein Ⅲ Alzheimer's disease Ⅲ cerebrovascular biology Ⅲ ␤ amyloid A lzheimer's disease (AD) is a chronic neurodegenerative disease affecting more than 5 million persons in the United States and more than 20 million worldwide. 1 AD is characterized by progressive loss of neurons, cognitive decline, and 2 defining histopathologies: extracellular amyloid plaques and intracellular tangles composed primarily of amyloid ␤ (A␤) peptide and hyperphosphorylated tau, respectively. 2 Furthermore, AD is often accompanied by cerebrovascular dysfunction, as well as amyloid deposition within the cerebral vessels, termed cerebral amyloid angiopathy. 3 A␤ is generated from sequential cleavages of its parent molecule, the amyloid precursor protein (APP), by the activities of ␤-site APP-cleaving enzyme (BACE)1 and ␥ secretase. 4,5 Importantly, A␤ has been shown to exert a plethora of effects on endothelial phenotype, including angiogenesis, proliferation, adhesion, and responsiveness to vasoactive molecules. 6,7 Moreover, it has been suggested that APP has functional roles in coagulation, adhesion, and inflammation. 8 The exact etiology of sporadic AD is unclear, but it is interesting that cardiovascular risk factors including hypertension, hypercholesterolemia, diabetes mellitus, aging, and sedentary lifestyle are associated with higher incidence of AD. 9 The link between cardiovascular risk factors and AD has yet to be identified; however, a common feature is endothelial dysfunction, specifically, decreased bioavailability of nitric oxide (NO). 10 In the cerebral circulation, endothelial NO is generated by endothelial nitric oxide synthase (eNOS), which, under basal conditions, is expressed exclusively in endothelial cells. 11 NO is an extremely important signaling molecule responsible for maintaining vascular homeostasis by promoting vasodilatation, inhibiting platelet aggregation and leukocyte adhesion. 12 Taken together, these data suggest that NO availability may be a common link between cardiovascular risk factors and the development of AD; therefore, we examine here the role of endothelial-derived NO in modulating brain and microvascular APP expression and processing and generation of the amyloidogenic fragment A␤. Methods and Results:

Hypertension Accelerates the Progression of Alzheimer-Like Pathology in a Mouse Model of the Disease

“…A recent evidence indicates that NO may protect against increase in Aβ through decreasing the levels of APP and APP-cleaving enzyme, β-secretase. 25 The observed increase of the levels of soluble Aβ in AD&HT mice might, therefore, result from the upregulation of APP and β-secretase, consecutive to the reduction of NO production in the brain. Moreover, Aβ42 levels may be regulated by angiotensin-converting enzyme which has been shown to cleave Aβ42 at several sites, including the resulting formation of Aβ40.…”

Occludin deficiency with BACE1 elevation in cerebral amyloid angiopathy

“…Recently, one study reported that mouse microvascular cells in cultures express BACE1. 21 To examine whether BACE1 was present in human cerebral vessels in vivo, especially in the cerebral vessels from CAA, a double-labeling immunohistochemical technique was performed in the brains with CAA. We found BACE1 expression in human cortical vessels identified with 2 vessel markers: a-SM actin and collagen IV (figure 1B).…”

Beneficial effects of lifelong caloric restriction on endothelial function are greater in conduit arteries compared to cerebral resistance arteries

“…With advancing age, endothelial dysfunction primarily results from reduced nitric oxide (NO) bioavailability (Taddei et al 2001). Not only is NO the key dilator produced by the endothelium (Vanhoutte 2003), but endothelial-derived NO can also decrease the expression of amyloid precursor proteins (Austin et al 2010), the accumulation of which is a characteristic feature of Alzheimer's disease (O'Brien and Wong 2011). Reactive oxygen species, particularly superoxide, reduce NO bioavailability and oxidative stress has been implicated as a major factor leading to impaired EDD with aging (Taddei et al 2001).…”