New Insights into Possible Role of NOS-NO-ADMA Pathway Dysfunction in the Development of Cognitive Decline and Dementia: Exploring the Vascular Features of Alzheimer’s Disease

Abstract

In recent years significant overlap between cardio-metabolic risk factors and cognitive decline has been reported. Cardio-metabolic and vascular factors shown to be associated with Alzheimer's disease (AD) and other forms of dementia include midlife diabetes and hypertension, cerebrovascular lesions, diminished vascular function, dyslipidemia, obesity, and cigarette smoking. Accordingly, it has been recently proposed that amyloid is not the cause of AD but merely a marker and a later consequence of upstream changes that lead to neuronal and synaptic losses. However, although the idea that features of vascular dysfunction and injury are present in cognitive decline and AD patients was suggested over 25 years ago, the role of cardio-metabolic and cerebrovascular mechanisms in the pathogenesis of AD is far from being fully elucidated. Based on newly proposed vascular hypothesis, there is an impaired structure and function of cerebral blood vessels and cells in patients with cognitive decline and AD which is mediated by vascular oxidative stress. Consistent with these observations, the importance of endothelial dysfunction in the development of AD has been highlighted. One of the most prominent features of endothelial dysfunction is decreased production and bioavailability of Nitric Oxide (NO). Based on versatile properties in physiological as well as in pathophysiological conditions NO is regarded as a key molecule for longevity and cardiovascular health. NO is produced by three different isoforms of the enzyme NO synthase (NOS), namely: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS). Reduced NO bioavailability and altered vascular expression and activity of NOS enzymes are implicated as major molecular players in the process of vascular aging. In the process of aging, the mechanisms by which NOS enzymes promote vascular dysfunction are specific for each NOS isoform. Normal activity of eNOS is required for the balanced production/bioavailability of NO, which is the main prerequisite for optimal vascular function. Conversely, excessive amount of NO produced by iNOS contributes to vascular dysfunction. Furthermore, although the possible role of nNOSderived NO in aging-associated vascular dysfunction is far from being fully elucidated, experimental findings indicate that impaired perivascular NO release from nNOS increases vasoconstriction in aged arterioles. Oxidative stress and inhibitors of NO synthase are regarded as most potent initiators of disturbed production and bioavailability of NO. Important endogenous inhibitor of all three isoforms of NOS is asymmetrical dimethylarginine (ADMA). It has been recently proposed that ADMA may be a possible link between vascular disease and dementia. Based on this assumption ADMA might represent a unifying pathophysiological pathway linking the presence of vascular risk factors with the onset and progression of cognitive decline and dementia. These observations were made based on good evidence from literature that higher plasma ADMA concentrations favor ath...

Targeted metabolomic analysis of nitric oxide/L-arginine pathway metabolites in dementia: association with pathology, severity, and structural brain changes

“…Noteworthy, contradicting results concerning ADMA have even been reported by the same group 11,24 stressing ADMA level dependence on cohort characteristics. The ADMA accumulation is expected in the conditions of oxidative stress and inflammation as a result of the up-regulated expression of PRMT enzymes (increased rate of ADMA synthesis) and the down-regulated expression of DDAH enzymes (decreased rate of ADMA degradation) 7 . However, Morales et al .…”

“…Brain homeostasis is secured by the activity of endothelial and neuronal isoforms of nitric oxide synthase (respectively eNOS and nNOS), catalyzing a two-step oxidation of L-arginine to NO and L-citrulline 7 . The NOS enzymes are negatively regulated by methylated derivatives of L-arginine.…”

“…SDMA is mainly excreted by the kidneys while ADMA is catabolized to L-citrulline and dimethylamine (DMA) by dimethylarginine dimethylaminohydrolases (DDAH). L-citrulline can serve as a substrate for endogenous synthesis of arginine 7 .…”

The Roles of Nitric Oxide Synthase/Nitric Oxide Pathway in the Pathology of Vascular Dementia and Related Therapeutic Approaches

“…Some studies have detected changes in the expression and activity of NO metabolites, donors, and NOS/NO itself in the brains of AD and VaD patients [ 82 , 83 , 84 ]. A review on animal stroke models showed that a supplemented NO donor improves overall CBF and reduces infarct size [ 85 ].…”

“…These results suggest that these three NOS subtypes play completely different roles in their respective regions and collectively affect the functions of brain. Currently, it has been proven that alterations of the NOS/NO pathway in VaD pathology manifest as a decrease of eNOS activity and the excessive activation of nNOS and iNOS [ 79 , 82 ].…”