5,15

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

Asija Zaciragic

CorrespAsija Zaciragic, Department of Human Physiology, School of Medicine University of Sarajevo, Cekalusa 90, 71000 Sarajevo, Bosnia and Herzegovina

Correspondence to: Asija Zaciragic, Department of Human Physiology, School of Medicine University of Sarajevo, Cekalusa 90, 71000 Sarajevo, Bosnia and Herzegovina
Email: zarias@lol.ba
Telephone: + 387-33-203670
Received: February 10, 2015
Revised: June 16, 2015
Accepted: July 21, 2015
Published online: December 1, 2015

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 nNOS-derived 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 atherosclerosis and independently predict adverse cardiovascular and cerebrovascular outcomes in several patient groups. However, possible role of ADMA in pathophysiology of cognitive decline and AD is still not fully understood. Prospective studies are warranted aiming at further clarification of ADMA involvement in development and progression of dementia. Moreover, use of ADMA in CSF and /or plasma as prospective biomarker of AD should be explored. According to newly introduced hypothesis disturbed NOS-NO-ADMA pathway is one of the most important attributes of cerebrovascular dysfunction that plays a pathogenic role in the development of cognitive decline and dementia. Experimental data from cell cultures and animal models have demonstrated that dysfunction of the NO-NOS- ADMA pathway results in cell death, blood-brain barrier (BBB) disruption, and brain edema via different pathological mechanisms. However, exact underlining mechanisms through which disturbed NOS-NO-ADMA pathway contributes to cognitive decline and dementia remain to be elucidated. Clarification of these mechanisms may be helpful in the identification of new therapeutic targets for aging and neurodegenerative diseases. Future research should also explain whether endothelial dysfunction precede or follow neurological changes which characterize cognitive decline and dementia. Moreover, clinical and epidemiological studies have shown that healthy nutrition and physical exercise are important non-pharmacological, lifestyle-related interventions that could help in maintaining appropriate vascular tone, adequate cerebral blood flow and normal cognition during aging. It is reasonable to suggest that prevention of cardio-metabolic diseases via endorsement of healthy aging determinants such as control of blood pressure, lipids and glucose levels as well as maintenance of optimal body weight achieved by regular physical activity and nutrition with high anti-oxidant capacity might be effective strategy in the preservation of cognitive function.

© 2015 ACT. All rights reserved.

Key words:Nitric Oxide (NO); Nitric Oxide Synthase (NOS); asymmetrical dimethylarginine (ADMA); NOS-NO-ADMA pathway dysfunction, cognitive decline; Dementia; Alzheimer’s disease

Zaciragic A. 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. International Journal of Neurology Research 2015; 1(4): 191-195 Available from: URL: http://www.ghrnet.org/index.php/ijnr/article/view/1067

REVIEW

In recent years significant overlap between cardio-metabolic risk factors and cognitive decline has been reported. Accordingly, numerous studies have demonstrated that midlife diabetes and hypertension predispose individuals to Alzheimer’s disease (AD) and vascular dementia[1-3]. Other cardio-metabolic and vascular factors shown to be associated with AD include cerebrovascular lesions, diminished vascular function, dyslipidemia, obesity, and cigarette smoking[4]. Although the idea that features of vascular dysfunction and injury are present in 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. Nevertheless, the linkage of vascular contributions to cognitive impairment and dementia has been now well recognized and there is necessity for better understanding how vascular factors contribute to development of AD and related dementias.

In this line of evidence, the significance of vascular contributions to cognitive impairment and dementia has been underlined in recently published Statement for Healthcare Professionals by the American Heart Association/American Stroke Association[5]. The American Academy of Neurology as well as The Alzheimer's Association supported the value of guidelines reported in this Statement as an important attempt in the understanding of causes of dementia as well as the factors that contribute to its progression. The authors of mentioned Statement have introduced term vascular cognitive impairment (VCI) in order to capture the entire spectrum of cognitive disorders associated with all forms of cerebral vascular brain injury ranging from mild cognitive impairment through fully developed dementia. Based on the reported findings within the Statement, cerebral amyloid angiopathy is emerging as an important marker of risk for AD and VCI. Authors propose that the neuropathology of cognitive impairment in later life is often a mixture of microvascular brain damage and classical AD features. Furthermore, mechanisms regulating cerebral blood flow as well as dysfunction of the neurovascular unit are suggested as important factors in VCI development.

Brain endothelial cells, pericytes or vascular smooth muscle cells, glia and neurons constitute the neurovascular unit (NVU) that controls blood–brain barrier (BBB) permeability and cerebral blood flow. Dysfunction of BBB results in reduction of cerebral blood flow and consequent hypoxia alongside with accumulation of diverse vasculotoxic and neurotoxic molecules within brain parenchyma[1]. All of these factors are thought to be associated with neurodegeneration seen in AD and related disorders.

Pathogenesis of Alzheimer's disease is multifactorial and still not known entirely. This most common form of dementia is neuropathologically characterized by presence of neurofibrillary tangles and senile neuritic plaques, amyloid-β peptid (Aβ) deposits and widespread neuronal loss. In everyday clinical practice reliable peripheral biochemical markers for diagnosis of AD are still not available and the disease itself can be manifested in wide range of neurological and psychiatric symptoms[4]. Hence, definitive diagnosis of AD can only be confirmed by postmortem examination of the brain that must contain sufficient number of plaques and tangles. Plaques are extracellular deposits of fibrils and amorphous aggregates of Aβ-peptide, whereas neurofibrillary tangles are intracellular fibrillar aggregates of the microtubule-associated protein tau which exhibits hyperphosphorylation and oxidative modifications[6]. Pivotal characteristic of AD brain is altered proteolytic processing of amyloid precursor protein (APP) that leads to the production and aggregation of neurotoxic forms of Aβ[4]. Thus, based on the “amyloid hypothesis”, the toxic cause of neural/synaptic damage and dementia is thought to be amyloid-β. However, 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[7]. According to this assumption impaired microvasculature, decreased cerebral blood flow and lack of vascular endothelial-derived trophic factors are causing atrophy of neural structures in already vulnerable brains of elderly with multiple age-related changes. Authors suggest that improvement of cerebral microvascular endothelial function may ameliorate the precipitating cause of AD and that future therapeutic strategies should focus on supporting normal angiogenesis.

Consistent with these observations, the importance of endothelial dysfunction in the development of AD has been highlighted in a recent review by Kelleher et al[8]. According to newly proposed vascular hypothesis, there is an impaired structure and function of cerebral blood vessels and cells in AD which is mediated by vascular oxidative stress. These changes can have detrimental effects on the cognitive function in patients with coexisting neurodegeneration.

Main features of vascular hypothesis for AD have been nicely summarized in a paper by Zlokovic[1]. In short, vascular risk factors lead to blood–brain barrier (BBB) dysfunction and a reduction in cerebral blood flow. These detrimental changes result in diminished amyloid-β clearance as well as in its increased production from the amyloid-β precursor protein with consequent amyloid- β accumulation. The increase in amyloid-β leads to neuronal dysfunction and injury causing cognitive dysfunction and neurodegeneration with consequent dementia.

Pivotal role in vascular hypothesis for AD development has been given to vascular/endothelial dysfunction that according to numerous evidences from literature is closely related to cognitive decline and dementia[9]. One of the most prominent features of endothelial dysfunction is decreased production and bioavailability of Nitric Oxide (NO).

Nitric oxide is a small, highly diffusible and reactive signaling molecule with a short life-time. NO mediates numerous physiologic processes including, among others, vasodilatation, regulation of immune response, neuronal development, neurotransmission, as well as memory and learning[10]. NO also regulates gene transcription and mRNA translation, and produces post-translational modifications of proteins[11].

NO is produced by three different isoforms of the enzyme NO synthase (NOS), namely: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS). These NOS isoforms can be distinguished by their origin from different genes, and they also have distinct tissue localization, as well as diverse properties including specific regulation and various sensitivity to inhibitors[12]. All three isoforms of NOS utilize L-arginine as the substrate whereas molecular oxygen and reduced nicotinamide-adenine-dinucleotide phosphate (NADPH) serve as co-substrates is the process of NO formation. Several cofactors are necessary for NO synthesis such as flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), and 5,6,7,8-tetrahydrobiopterin (BH4)[11].

Endothelial NOS (eNOS) apart from endothelial cells can also be found in cardiomyocytes, vascular smooth muscle cells, thrombocytes, lung epithelial cells, hepatocytes and others[13-15]. NO synthesized by eNOS has numerous physiological functions including vasodilatation, inhibition of thrombocyte adhesion and aggregation, as well as potent antiatherogenic effects[16].

Neuronal NOS (nNOS) is expressed in specific neurons of the central nervous system (CNS), but it can also be exprimed in hypophysis, skeletal muscles, kidneys, adrenal glands, skin, pancreatic islet cells, lung epithelial cells, vascular smooth muscle cells and other cells and tissues[17]. Significance of nNOS in diverse synaptic signaling events including neurotransmission and neuromodulation has been verified in numerous studies[18-21]. Learning, memory, neurogenesis, long-term regulation of synaptic transmission, as well as important role in stress and adaptive responses of the organism are some of the most prominent functions of nNOS-derived NO.

Both eNOS and nNOS isoforms are considered to be expressed constitutively and at least in some tissues their activity is Ca2+-dependent. Inducible NOS (iNOS) has been long thought to be Ca2+-independent and expressed only after induction under inflammatory conditions. After stimulation which requires a complex cytokine combination, a variety of cells are able to express iNOS including monocytes, mast cells, cardiac myocytes, vascular smooth muscle cells, hepatocytes or glial cells[22,23]. Contrary to earlier opinion, it is now known that some specific cells such as human airway epithelium also show constitutive expression of iNOS. Expression of iNOS can be further promoted by presence of certain factors such as oxidative stress and, on the contrary, be suppressed by glucocorticoid treatment[12]. Upon induction, high amount of iNOS-derived NO is produced with cytotoxic effects in antiviral, antimicrobial, antiparasitic and tumoricidal processes. NO produced by iNOS is thought to mediate inflammation and non-specific immune defense and also has important role in septic shock[24-26].

Although NO has numerous functions within human body, best studied and confirmed so far are those in vasculature and central nervous system. Studies have shown that constitutively synthesized NO plays an obligatory role in maintaining vascular homeostasis in the cerebral circulation[27]. One of the most prominent features of cerebrovascular dysfunction seen in AD is cerebral hypoperfusion/hypoxia with impaired NO release[28].

Reduced NO bioavailability and altered vascular expression and activity of NOS enzymes are implicated as major molecular players in the process of vascular aging. The term vascular aging reflects structural and functional disturbances of the vasculature with advancing age[29]. It is of note that 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. Results from experimental studies suggest that decreased NO bioavailability as well as increased reactive nitrogen species (RNS) production contribute to aging-associated vascular dysfunction[30]. Furthermore, although the possible role of nNOS-derived 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[31,32]. Based on versatile properties in physiological as well as in pathophysiological conditions NO is regarded as a key molecule for longevity and cardiovascular health.

Possible role of disturbed production and bioavailability of NO in the development and progression of dementia has been suggested by Colton et al[33] based on the findings from the study in a mouse model of Alzheimer’s disease. Reduced synthesis and availability of endothelial NO may contribute to the development of dementia by at least two mechanisms: favoring the onset and progression of atherosclerosis, vasoconstriction, and impaired cerebral blood flow regulation; and by reduced neuroprotection[34].

Oxidative stress and inhibitors of NO synthase are regarded as most potent initiators of disturbed production and bioavailability of NO[35]. Important endogenous inhibitor of all three isoforms of NOS is asymmetrical dimethylarginine (ADMA)[36]. Most prominent feature of ADMA actions besides inhibition of NO synthesis is promotion of oxidative stress and vascular damage[34]. Moreover, ADMA is regarded as reliable non-invasive marker of endothelial dysfunction. Accordingly, studies conducted so far have shown increased plasma levels of ADMA in numerous diseases related to endothelial dysfunction such as coronary heart disease, hypercholesterolemia, hypertension and diabetes mellitus[37]. However, only few studies so far have been evaluating alterations of ADMA concentrations related to cognitive decline and AD.

Results of a large case-control study including 80 AD patients and 80 healthy controls, matched for age, body mass index (BMI), and gender conducted by Arlt et al[35] have shown increased plasma ADMA concentration but decreased ADMA concentration in cerebrospinal fluid (CSF) of AD patients. Furthermore, significant association between decreasing ADMA levels in CSF and the severity of cognitive impairment was observed. One of the most important findings of this study is that CSF and plasma ADMA levels are independently regulated and have to be regarded separately. In short, based on obtained data authors suggest that decreased ADMA levels in CSF might be related to oxidative stress and protein damage through increased peroxynitrite production in the brain. On the other hand, increased plasma ADMA concentration levels might independently contribute to AD pathophysiology by decreasing brain microperfusion.

Importance of decreased cerebrovascular perfusion as contributing factor to AD pathology has been suggested by other authors as well[38-40]. In line with these remarks, Asif et al[34] recently proposed ADMA as a possible link between vascular disease and dementia. Authors suggested that ADMA might represent a unifying pathophysiological pathway linking the presence of vascular risk factors with the onset and progression of cognitive decline and dementia. Their observations were made based on good evidence from literature that higher plasma ADMA concentrations favor atherosclerosis and independently predict adverse cardiovascular and cerebrovascular outcomes in several patient groups.

However, possible role of ADMA in pathophysiology of cognitive decline and AD is far from being fully elucidated. Prospective studies are warranted aiming at further clarification of ADMA involvement in development and progression of dementia. Moreover, use of ADMA in CSF and /or plasma as prospective biomarker of AD should be explored. In difference to NO measurement, potential usefulness of ADMA as possible biomarker of cognitive decline is reflected by its relative stable concentration in plasma which can be accurately measured.

Previous studies have shown that disturbed NOS-NO-ADMA pathway is closely related to endothelial dysfunction which has pivotal role in the development of cardio-metabolic diseases[41]. Furthermore, according to recently introduced hypothesis disturbed NOS-NO-ADMA pathway is also one of the most important attributes of cerebrovascular dysfunction that plays a pathogenic role in the development of cognitive decline and dementia. Experimental data from cell culture and animal models have demonstrated that dysfunction of the NO-NOS- ADMA pathway results in cell death, blood-brain barrier (BBB) disruption, and brain edema via different pathological mechanisms[42]. However, exact underlining mechanisms through which disturbed NOS-NO-ADMA pathway contributes to cognitive decline and dementia remain to be elucidated. Clarification of these mechanisms may be helpful in the identification of new therapeutic targets for aging and neurodegenerative diseases.

In summary, numerous findings indicate that cardio-metabolic and vascular risk factors, as well as advanced aging contribute to the development of endothelial dysfunction. The main features of endothelial dysfunction are reduced eNOS activity, decreased NO production, increased NO degradation as well as increased plasma ADMA levels. Within brain vasculature endothelial dysfunction results in hypoperfusion leading to reduced oxygen supply, metabolic dysfunction, increased amyloid-ß accumulation and enhanced production of reactive oxygen species. These detrimental processes are thought to be associated with neurodegeneration, apoptosis, cognitive failure and memory loss[27]. According to present notion, important role in this setting has disturbed NOS-NO-ADMA pathway. However, more basic and clinical research on the vascular features of cognitive dysfunction and AD is required. Future research should also clarify whether endothelial dysfunction precede or follow neurological changes which characterize cognitive decline and dementia.

Based on the findings summarized in this paper, increasing evidence point to significant role of endothelial dysfunction in the pathogenesis of cognitive decline and dementia. Both cognitive decline and dementia are related to cardio-metabolic risk factors which is well documented in the literature. Clinical and epidemiological studies have shown that healthy nutrition and physical exercise are important non-pharmacological, lifestyle-related interventions that could help in maintaining appropriate vascular tone, adequate cerebral blood flow and normal cognition during aging[43]. It is reasonable to suggest that prevention of cardio-metabolic diseases via endorsement of healthy aging determinants such as control of blood pressure, lipids and glucose levels as well as maintenance of optimal body weight achieved by regular physical activity and nutrition with high anti-oxidant capacity might be effective strategy in the preservation of cognitive function.

CONFLICT OF INTERESTS

There are no conflicts of interest with regard to the present study.

REFERENCES

1.Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci. 2011;12(12):723-738.

2.Iadecola C, Davisson RL. Hypertension and cerebrovascular dysfunction. Cell Metab. 2008;7:476–484.

3.Luchsinger JA, Reitz C, Patel B, Tang MX, Manly JJ, Mayeux R. Relation of diabetes to mild cognitive impairment. Arch Neurol. 2007;64(4):570-575.

4.Zaciragic A. Different Approaches in the Treatment of Alzheimer's Disease: Comprehensive Insight. In: Frontiers in Clinical Drug Research – Alzheimer Disorders. Vol.1. Bentham Sciences Publisher e-Book; 2014: 183-216.

5.Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C, Launer LJ, Laurent S, Lopez OL, Nyenhuis D, Petersen RC, Schneider JA, Tzourio C, Arnett DK, Bennett DA, Chui HC, Higashida RT, Lindquist R, Nilsson PM, Roman GC, Sellke FW, Seshadri S; American Heart Association Stroke Council, Council on Epidemiology and Prevention, Council on Cardiovascular Nursing, Council on Cardiovascular Radiology and Intervention, and Council on Cardiovascular Surgery and Anesthesia. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American heart association/American stroke association. Stroke. 2011;42(9):2672-2713.

6.Mattson MP. Pathways towards and away from Alzheimer's disease. Nature. 2004;430(7000):631-639.

7.Drachman DA. The amyloid hypothesis, time to move on: Amyloid is the downstream result, not cause, of Alzheimer's disease. Alzheimers Dement. 2014;10(3):372-380.

8.Kelleher RJ, Soiza RL. Evidence of endothelial dysfunction in the development of Alzheimer's disease: Is Alzheimer's a vascular disorder? Am J Cardiovasc Dis. 2013;3(4):197-226.

9.Bomboi G1, Castello L, Cosentino F, Giubilei F, Orzi F, Volpe M. Alzheimer's disease and endothelial dysfunction. Neurol Sci. 2010;31(1):1-8.

10.Santos RM, Lourenço CF, Ledo A, Barbosa RM, Laranjinha J. Nitric oxide inactivation mechanisms in the brain: role in bioenergetics and neurodegeneration. Int J Cell Biol. 2012;2012:391914.

11.Förstermann U, Sessa WC. Nitric oxide synthases: regulation and function. Eur Heart J. 2012;33(7):829-837.

12.Kopincová J, Púzserová A, Bernátová I. Biochemical aspects of nitric oxide synthase feedback regulation by nitric oxide. Interdiscip Toxicol. 2011;4(2):63-68.

13.Förstermann U, Boissel JP, Kleinert H. Expressional control of the ‚constitutive‘ isoforms of nitric oxide synthase (NOS I and NOS III). FASEB J 1998;12:773–790.

14.Arnal JF, Dinh-Xuan AT, Pueyo M, Darblade B, Rami J. Endothelium-derived nitric oxide and vascular physiology and pathology. Cell Mol Life Sci 1999;55: 1078–1087.

15.Strapková A, Antošová M, Nosáľová G. Effect of NO-synthase and arginase inhibition in airway hyperreactivity. Bratisl Lek Listy 2008;109:191–197.

16.Esper RJ, Nordaby RA, Vilariño JO, Paragano A, Cacharrón JL, Machado RA. Endothelial dysfunction: a comprehensive appraisal. Cardiovasc Diabetol 2006;5:4.

17.Förstermann U, Closs EI, Pollock JS, Nakane M, Schwarz P, Gath I, Kleinert H. Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions. Hypertension 1994;23:1121–1131.

18.O’Dell TJ, Hawkins RD, Kandel ER, Arancio O. Tests of the roles of two diffusible substances in long-term potentiation: evidence for nitric oxide as a possible early retrograde messenger. Proc Natl Acad Sci USA 1991;88:11285–11289.

19.Schuman EM, Madison DV. A requirement for the intercellular messenger nitric oxide in long-term potentiation. Science 1991;254:1503–1506.

20.Izumi Y, Clifford DB, Zorumski CF. Inhibition of long-term potentiation by NMDA-mediated nitric oxide release. Science 1992;257:1273–1276.

21.Izumi Y, Zorumski CF. Nitric oxide and long-term synaptic depression in the rat hippocampus. Neuroreport 1993;4:1131–1134.

22.Michel T, Feron O. Nitric oxide synthases: which, where, how, and why? J Clin Invest 1997;100:2146–2152.

23.Aktan F. iNOS-mediated nitric oxide production and its regulation. Life Sci 2004;75: 639–653.

24.Bogdan C. Nitric oxide and the immune response. Nat Immunol 2001;2:907–916.

25.Rafiee P, Ogawa H, Heidemann J, Li MS, Aslam M, Lamirand TH, Fisher PJ, Graewin SJ, Dwinell MB, Johnson CP, Shaker R, Binion DG. Isolation and characterization of human esophageal microvascular endothelial cells: mechanisms of inflammatory activation. Am J Physiol Gastrointest Liver Physiol 2003;285:G1277–G1292.

26.Wong JM, Billiar TR. Regulation and function of inducible nitric oxide synthase during sepsis and acute inflammation. Adv Pharmacol 1995;34:155–170.

27.Toda N, Okamura T. Cerebral blood flow regulation by nitric oxide in Alzheimer's disease. J Alzheimers Dis. 2012;32(3):569-578.

28.Toda N, Ayajiki K, Okamura T. Cerebral blood flow regulation by nitric oxide in neurological disorders. Can J Physiol Pharmacol 2009;87:581-594.

29.Herrera MD, Mingorance C, Rodriguez-Rodriguez R, Alvarez de Sotomayor M. Endothelial dysfunction and aging: an update. Ageing Res.Rev. 2010;9:142–152.

30.Cau SB, Carneiro FS, Tostes RC. Differential modulation of nitric oxide synthases in aging: therapeutic opportunities. Front Physiol. 2012;3:218.

31.Ferrer M, Balfagón G. Aging alters neuronal nitric oxide release from rat mesenteric arteries: role of presynaptic beta-adrenoceptors. Clin Sci (Lond). 2001;101(4):321-328.

32.Ferrer M, Sánchez M, Minoves N, Salaices M, Balfagón G. Aging increases neuronal nitric oxide release and superoxide anion generation in mesenteric arteries from spontaneously hypertensive rats. J Vasc Res. 2003;40(6):509-519.

33.Colton CA, Vitek MP, Wink DA, Xu Q, Cantillana V, Previti ML, Van Nostrand WE, Weinberg JB, Dawson H. NO synthase 2 (NOS2) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2006;103(34):12867-12872.

34.Asif M, Soiza RL, McEvoy M, Mangoni AA. Asymmetric dimethylarginine: a possible li

nk between vascular disease and dementia. Curr Alzheimer Res. 2013;10(4):347-356.

35.Arlt S, Schulze F, Eichenlaub M, Maas R, Lehmbeck JT, Schwedhelm E, Jahn H, Böger RH. Asymmetrical dimethylarginine is increased in plasma and decreased in cerebrospinal fluid of patients with Alzheimer's disease. Dement Geriatr Cogn Disord. 2008;26(1):58-64.

36.Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 1992; 339:572–575.

37.Alpoim PN, Sousa LP, Mota AP, Rios DR, Dusse LM. Asymmetric Dimethylarginine (ADMA) in cardiovascular and renal disease. Clin Chim Acta. 2015;440C:36-39.

38.de la Torre JC. Alzheimer disease as a vascular disorder: nosological evidence. Stroke 2002;33:1152–1162.

39.Selley ML. Increased concentrations of homocysteine and asymmetric dimethylarginine and decreased concentrations of nitric oxide in the plasma of patients with Alzheimer’s disease. Neurobiol Aging 2003;24:903–907.

40.Zhao Y, Gong CX. From chronic cerebral hypoperfusion to Alzheimer-like brain pathology and neurodegeneration. Cell Mol Neurobiol. 2015;35(1):101-110.

41.Musa MG, Torrens C, Clough GF. The microvasculature: a target for nutritional programming and later risk of cardio-metabolic disease. Acta Physiol (Oxf). 2014;210(1):31-45.

42.Li N, Worthmann H, Deb M, Chen S, Weissenborn K. Nitric oxide (NO) and asymmetric dimethylarginine (ADMA): their pathophysiological role and involvement in intracerebral hemorrhage. Neurol Res. 2011; 33(5):541-548.

43.Kalaria RN, Akinyemi R, Ihara M. Does vascular pathology contribute to Alzheimer changes? J Neurol Sci. 2012;322(1-2):141-147.

Peer reviewer:Jingli Zhang, MD,PhD, Senior Lecturer, Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kota Bahru, Kelantan, Malaysia.

Refbacks

  • There are currently no refbacks.