Aberrant expression of nitric oxide synthase III in Alzheimer's disease: relevance to cerebral vasculopathy and neurodegeneration

Alzheimer's disease (AD) has heterogeneous pathology, in parr due to the la rge subset of cases (AD+CVD) with superimposed vascular lesions that are su fficient in number and distribution to accelerate the clinical course of de mentia. Brains with AD+CVD have lower densities of neurofibrillary tangles and A beta-amyloid diffuse plaques, and increased numbers of cerebral vesse ls exhibiting p53-associated apoptosis relative to brains with uncomplicate d AD. AD and AD+CVD both exhibit altered expression of the nitric oxide syn thase 3 (NOS-III) gene; however, in AD+CVD, reduced NOS-III expression in c erebral vessels is associated with an increased frequency of vascular lesio ns, vascular smooth muscle cell apoptosis, and A beta-amyloid plaques. In c ontrast, experimental and spontaneous focal acute and subacute cerebral inf arcts are associated with increased NOS-III expression in perifocal neurons , glial cells, cerebrovascular smooth muscle and endothelial cells, and dif fuse A beta-amyloid plaque formation. This suggests that ischemic injury an d oxidative stress can precipitate NOS-III-mediated cell loss and neurodege neration. A role for aging-associated impaired mitochondrial function as a contributing factor in AD and CVD is suggested by the reduced levels of mit ochondrial protein observed in AD and AD+CVD cortical neurons and vascular smooth muscle and endothelial cells. The aggregate findings suggest that ce ll loss and neurodegeneration may be mediated by somewhat distinct but over lapping mechanisms in AD and AD+CVD. (C) 2000 Elsevier Science Inc. All rig hts reserved.