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Role of aberrant nitric oxide synthase-3 expression in cerebrovascular degeneration and vascular-mediated injury in Alzheimer's disease.

Abstract：

:Nitric oxide (NO) is an important signaling molecule that is generated through the catalytic activity of nitric oxide synthase (NOS). In the brain, NO mediates neuronal survival, synaptic plasticity, vascular smooth muscle relaxation, and endothelial cell permeability. Previous studies demonstrated aberrant expression of the NOS-III gene in neurons and glial cells in brains with Alzheimer's disease (AD). Since NOS-III is also expressed in vascular cells, and cerebrovascular disease (CVD) frequently complicates the pathology of AD, we investigated the role of NOS-III in relation to CVD in AD. Vasculopathy in AD + CVD was characterized by thickening and hyalinization of the media of small and medium-size vessels, variable degrees of beta-amyloid (A beta) deposition, and increased apoptosis of vascular smooth muscle and endothelial cells, particularly involving white matter vessels. These abnormalities were correlated with reduced levels of NOS-III expression in cerebral vessels. Double-labeling studies demonstrated that the low levels of cerebrovascular NOS-III were associated with increased levels of the pro-apoptosis gene product, p53 in smooth muscle and endothelial cells, suggesting a role for altered NOS-III expression in AD-associated vascular degeneration. Constitutively reduced cerebrovascular NOS-III expression and NO production could also lead to cerebral hypoperfusion due to impaired vasodilation responses, and diminished capacity to remove respiratory waste products and toxins from the extracellular space due to reduced capillary permeability. The role for phosphodiesterases as modulators of NOS activity is discussed, as these molecules represent potential therapeutic targets given their cell type and cyclic nucleotide specificities of action.

journal_name

Ann N Y Acad Sci

journal_title

Annals of the New York Academy of Sciences

authors

de la Monte SM,Sohn YK,Etienne D,Kraft J,Wands JR

doi

10.1111/j.1749-6632.2000.tb06351.x

subject

Has Abstract

pub_date

2000-04-01 00:00:00

pages

61-71

eissn

0077-8923

issn

1749-6632

journal_volume

903

pub_type

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Role of aberrant nitric oxide synthase-3 expression in cerebrovascular degeneration and vascular-mediated injury in Alzheimer's disease.