Elsevier

Neurobiology of Aging

Volume 21, Issue 2, March–April 2000, Pages 309-319
Neurobiology of Aging

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

https://doi.org/10.1016/S0197-4580(99)00108-6Get rights and content

Abstract

Alzheimer’s disease (AD) has heterogeneous pathology, in part due to the large subset of cases (AD+CVD) with superimposed vascular lesions that are sufficient in number and distribution to accelerate the clinical course of dementia. Brains with AD+CVD have lower densities of neurofibrillary tangles and Aβ-amyloid diffuse plaques, and increased numbers of cerebral vessels exhibiting p53-associated apoptosis relative to brains with uncomplicated AD. AD and AD+CVD both exhibit altered expression of the nitric oxide synthase 3 (NOS-III) gene; however, in AD+CVD, reduced NOS-III expression in cerebral vessels is associated with an increased frequency of vascular lesions, vascular smooth muscle cell apoptosis, and Aβ-amyloid plaques. In contrast, experimental and spontaneous focal acute and subacute cerebral infarcts are associated with increased NOS-III expression in perifocal neurons, glial cells, cerebrovascular smooth muscle and endothelial cells, and diffuse Aβ-amyloid plaque formation. This suggests that ischemic injury and oxidative stress can precipitate NOS-III-mediated cell loss and neurodegeneration. A role for aging-associated impaired mitochondrial function as a contributing factor in AD and CVD is suggested by the reduced levels of mitochondrial protein observed in AD and AD+CVD cortical neurons and vascular smooth muscle and endothelial cells. The aggregate findings suggest that cell loss and neurodegeneration may be mediated by somewhat distinct but overlapping mechanisms in AD and AD+CVD.

Introduction

The pathology of AD is heterogeneous due to highly variable densities of senile plaques, Aβ-amyloid deposits, and neurofibrillary tangles, and overlapping neurodegeneration of Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), or diffuse Lewy body disease (DLBD) [23]. In addition, recent evidence indicates that cerebrovascular disease (CVD) and associated hemispheric infarcts, lacunes, hippocampal sclerosis, and leukoaraiosis may contribute substantially to the clinical manifestations of dementia in AD [10], [19], [21], [28], [37], [41], [57], [69], [82], [95], [108]. Postmortem and neuroimaging studies demonstrated that AD may be complicated by vascular pathology in 20 to 40% of the cases [10], [21], [28], [108], yet clinically, AD and AD+CVD have not been distinguished. Survey of the of the Massachusetts General Hospital Alzheimer’s Disease Research Center (MGH-ADRC) Brain Bank archives revealed the presence of multiple small (microscopic) cerebral infarcts in approximately 30% of the AD cases [25]. In another large study, CVD was detected in 17% of the AD cases, and significant AD neurodegenerative pathology was found in 55% of the cases diagnosed with vascular dementia [95]. The failure to recognize the protean nature of lesions that can be associated with AD is likely responsible for under-diagnosis of AD+CVD.

Like AD, CVD increases with age and is most prevalent in individuals between ages 60 and 75 years. Neuronal loss and synaptic disconnection are responsible for the clinical deficits associated with both AD and cerebral infarction. Therefore, lesions caused by CVD could exacerbate the clinical course and contribute to the heterogeneity of AD. For examples, individuals with early, subclinical AD may develop cognitive impairment or dementia due to ischemic lesions and infarcts in structures typically damaged by AD neurodegeneration [69]. If cerebral infarction does contribute to the progression of AD, early detection, treatment, and attention to probable risk factors such as systemic hypertension, history of repeated stroke-like episodes, impaired vaso-responsiveness, evidence of cerebral hypoperfusion as demonstrated by functional imaging studies, and Apolipoprotein E-ϵ4 genotype [5], [19], [39], [42], [63], [72], [78], [106] may help prevent, delay, or mollify the clinical course of AD-type dementia in a substantial percentage of the cases.

Section snippets

Neurodegenerative and vascular lesions in AD and AD+CVD

To determine the role of cerebrovascular lesions in AD-type dementia, the densities of Bielschowsky-stained senile plaques and neurofibrillary tangles, and the distribution and extent of vascular lesions were compared in AD and AD+CVD using cases from the MGH-ADRC brain bank archives [25]. The cases were matched for age, gender, and severity of dementia. Brains classified as AD+CVD had multiple vascular lesions consisting of microscopic ischemic infarcts, foci of white matter pallor

Comparison of Aβ-amyloid pathology in AD and AD+CVD

To determine the relative role of Aβ-amyloid angiopathy in AD compared with AD+CVD, histological sections of frontal (Area 11) and temporal (Area 21) lobe were immunostained to detect and quantify the distribution of Aβ-amyloid-immunoreactive lesions. Aβ-amyloid was observed in diffuse plaques, dense core (mature) plaques, and smooth muscle cells in the media of small and medium sized vessels within the leptomeninges and superficial cerebral cortex. The densities of Aβ-amyloid plaques were

Pro-apoptosis gene expression is associated with Aβ-amyloid deposits in vessels and senile plaques

Experimentally, Aβ-amyloid [46] and some forms of mutant amyloid precursor protein expressed in familial AD [103] are neurotoxic and induce neuronal apoptosis. In addition, increased expression of the pro-apoptosis gene products p53 and Bax, is associated with Aβ-amyloid deposits in senile plaques [52]. Bax and p53-mediated apoptosis of neurons and glial cells are established mechanisms of cell loss in AD [18], [87]. p53 and Bax inhibit expression of Bcl-2, a cell survival gene product, thereby

Actions of nitric oxide synthase and NO in neuronal cells

Nitric oxide (NO) is a free radical gas that functions as an inter- and intracellular signaling molecule in the brain [77]. NO is generated from NO synthases (NOSs) through the oxidation of a guanidino nitrogen of l-arginine. Three NOS isoforms have been identified and divided into two functional classes: constitutive and inducible. The two constitutive isoforms, initially identified in neurons (NOS-I) and endothelial cells (NOS-III), are stimulated to synthesize NO by calcium/calmodulin

Aberrant NOS-III expression in Alzheimer’s disease: relevance to neurodegeneration

In AD, impaired synaptic plasticity and cell death are probably the underlying bases of dementia. Therefore abnormal NOS gene expression may represent an important mechanism of neurodegeneration in AD. The findings of preserved long-term potentiation in NOS I-deficient mice [62], sparing of NOS I-expressing neurons in AD [35], and deficits in long-term potentiation in mice with doubly deficient in the NOS-I and NOS-III genes in the CNS [84], led us to characterize NOS-III expression in AD and

Mechanisms of nitric oxide-induced functional modulation of vascular smooth muscle and endothelial cells

Nitric oxide causes relaxation of vascular smooth muscle cells leading to vasodilation and increased blood flow. Transgenic mice depleted of the NOS-III gene, although relatively spared of the excitotoxic effects of high levels of NO associated re-perfusion injury in the perifocal zones, exhibit increased intracerebral hemorrhage. The vascular smooth muscle responses to NO are mediated through activation of soluble guanylate cyclase and increased levels of cGMP. Down-stream signaling involves

Aberrant NOS-III expression and cerebral vasculopathy

In the normal brain, NOS-III immunoreactivity was readily detected in vascular endothelial and smooth muscle cells. In AD and AD+CVD, NOS-III expression in cerebral vessels was strikingly reduced and virtually undetectable in many small and medium-size leptomeningeal, cortical, and white matter vessels. Double-labeling studies demonstrated that aberrantly reduced NOS-III expression in AD and AD+CVD was associated with increased p53 and Aβ-amyloid in vascular smooth muscle cells. Constitutively

Modulation of vascular NOS-III with cerebral infarction

Although our hypothesis is that aberrant NOS-III expression contributes to CNS vascular lesions and neurodegeneration in AD and AD+CVD, we also considered whether vascular-mediated injury could inhibit NOS-III and help trigger cerebrovascular degeneration and apoptosis. Therefore, we examined NOS-III expression in the perifocal zones, and in regions distant from the infarcts in otherwise normal brains. The studies were conducted by using an experimental focal stroke model in rat brains [15],

Potential role of mitochondrial DNA damage as “the clock” for governing the onset of cellular and cerebrovascular degeneration in Alzheimer’s disease

NO is not a potent oxidant. However, when combined with O2-, the adverse effects of NO can be enhanced through generation of peroxynitrite (ONOO−), a potent cytotoxic oxidant [86]. O2- forms when free-radical scavenger availability is inadequate, oxidative stress are imposed by hypoxic/ischemic injury, or mitochondrial function is impaired. Recent evidence suggests that aging and a number of prevalent age-associated diseases, including cancer, heart disease, and neurodegeneration, may be

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      Being a largely irreversible protein modification, 3-NT is useful as a marker of nitrative stress, and is a common consequence of iNOS expression during inflammation. Glial iNOS was further shown to be increased around neurofibrillary tangles and amyloid lesions in AD brains, as well as in Aβ-stimulated glial cultures, in the latter case in an NF-κB dependent manner (Akama and Van Eldik, 2000; De La Monte et al., 2000; Pacher et al., 2007). Notably, 3-NT is also found increased in the CSF of AD patients, and its buildup is an early event, detected in those diagnosed with mild cognitive impairment, a preliminary condition that often progresses to AD (Butterfield et al., 2007; Pacher et al., 2007; Reed et al., 2009; Reynolds et al., 2006; Tohgi et al., 1999).

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