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

Monte, Suzanne M. de la; Lu, Bing-xun; Sohn, Yoon Kyung; Etienne, Dannie; Kraft, Joanny; Ganju, Neema; Wands, Jack R.

doi:10.1016/s0197-4580(99)00108-6

Cited by 54 publications

(22 citation statements)

References 95 publications

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“…FernandezVizarra et al (40) have shown that neuronal NOS protein levels aberrantly increase in AD neurons, whereas neuronal NOS activity in brain lysates is reduced. Increased expression of endothelial NOS in AD is also observed, but is primarily localized to the dystrophic neurites and astrocytes that surround amyloid plaques (11,41). Our quantitative PCR data support the idea that changes in constitutive NOS isoforms are unlikely to adequately compensate for the genetic loss of iNOS.…”

Section: Discussionsupporting

confidence: 74%

NO synthase 2 ( NOS2 ) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease

Colton¹,

Vitek²,

Wink

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

120

103

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Section: Discussionsupporting

confidence: 74%

NO synthase 2 ( NOS2 ) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease

Colton¹,

Vitek²,

Wink

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

120

103

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“…47 The NOS pathway has been implicated in the pathogenesis of Alzheimer's disease (AD), PD, and cerebrovascular disease and stroke, and previous studies have also demonstrated aberrant expression of the NOS3 gene in neurons, glial and endothelial cells in AD brains. [46][47][48] The Glu/Glu genotype at p.(Asp298Glu) (rs1799983; ClinVar pathogenic allele) has been reported as a risk factor for AD in several case-control studies.…”

Section: Discussionmentioning

confidence: 99%

Identification of candidate genes for familial early-onset essential tremor

et al. 2015

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Essential tremor (ET) is one of the most common causes of tremor in humans. Despite its high heritability and prevalence, few susceptibility genes for ET have been identified. To identify ET genes, whole-exome sequencing was performed in 37 early-onset ET families with an autosomal-dominant inheritance pattern. We identified candidate genes for follow-up functional studies in five ET families. In two independent families, we identified variants predicted to affect function in the nitric oxide (NO) synthase 3 gene (NOS3) that cosegregated with disease. NOS3 is highly expressed in the central nervous system (including cerebellum), neurons and endothelial cells, and is one of three enzymes that converts L-arginine to the neurotransmitter NO. In one family, a heterozygous variant, c.46G4A (p. (Gly16Ser)), in NOS3, was identified in three affected ET cases and was absent in an unaffected family member; and in a second family, a heterozygous variant, c.164C4T (p.(Pro55Leu)), was identified in three affected ET cases (dizygotic twins and their mother). Both variants result in amino-acid substitutions of highly conserved aminoacid residues that are predicted to be deleterious and damaging by in silico analysis. In three independent families, variants predicted to affect function were also identified in other genes, including KCNS2 (KV9.2), HAPLN4 (BRAL2) and USP46. These genes are highly expressed in the cerebellum and Purkinje cells, and influence function of the gamma-amino butyric acid (GABA)-ergic system. This is in concordance with recent evidence that the pathophysiological process in ET involves cerebellar dysfunction and possibly cerebellar degeneration with a reduction in Purkinje cells, and a decrease in GABA-ergic tone.

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“…Expression of eNOS has been examined in Alzheimer's disease with variable results. 15 One 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.…”

mentioning

confidence: 99%