Yes. There is considerable evidence that Alzheimer's is a consequence of low NO levels in the brain.

http://www.ncbi.nlm.nih.gov/pubmed/11113503

Hi Mohamed.

The group headed up by Roberts from the NCI have recently published a paper detailing NO signalling due to the inhibitory effect of Amyloid-β binding to the cell surface receptor CD36. This down regulation results in a reduction of brain vascular tone ultimately promoting neuronal toxicity. See paper referenced below:

Amyloid-β inhibits No-cGMP signaling in a CD36- and CD47-dependent manner.

Miller TW, Isenberg JS, Shih HB, Wang Y, Roberts DD

Nitrergic neurons have a great role in basal nuclei and hippocampus circuitary... It must have implications in AD.

It is a possibility that low levels of NO in CNS can be linked to AD

Just be careful because one should separate the origin of nitric oxide. If one regards the NO from the constitutives isoforms the answer is yes if one relates to the NO from iNOS the answer is no.

Toxic Breakups: The Deadly Relationship Between Alzheimer’s Disease

and Nitric Oxide Gas. Eukaryon, Vol. 7, March 2011, Lake Forest College

Thank you very much all of you for the valuable comments

NOS 2 is upregulated in Alzheimer disease. NO is implicated in the regulation of enzyme activity. For example:

http://www.ncbi.nlm.nih.gov/pubmed/22227962

I wonder how Alzheimer's is a consequence of low NO levels in the brain and in the same time one of the tools for experimental induction of Alzheimer is by lipopolysaccahride administration, a mechanism known to induce iNOS ?

The increased NO derived from iNOS leads to IDE inhibition and oxidative stress aggravating Alzheimer.

Something in my mind is that NO induces synatic dysfunctions. In terms of this, maybe AD is just one kind of dementia related to NO.

Please check the paper by Carl Nathan in JEM 2005 " Protection from Alzheimer's-like disease in the mouse by genetic ablation of inducible nitric oxide synthase". That should be a good start.

Constitutive release of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS) in cerebral vessels is crucial in maintaining basal tone. Stimulus-induced release of NO mediates vasodilation. Basal and stimulus-induced release of NO are integral to a healthy cerebral circulation, which is known to be compromised in AD. There is evidence in AD transgenic mice that free radicals sequester NO and compromise basal and stimulus-induced vasodilations. The inability of the brain to match blood flow demands to neuronal activity has been shown in AD. See many articles from the Edith Hamel lab in Montreal and Constantino Iadecola lab in the US.

Thank you Emil and Nekatria for your comments. I am still wondering how both the decrease in NO made by eNOS or nNOS and increase in NO made by iNOS lead to the same conclusion, neurodegeneration and AD.

I think it is a good example of how a molecule is not good or bad in itself, but also of how we must think of molecules within pathways cross-talking with each other, rather than as isolated molecules and events. It is likely that disrupted homeostasis within neuronal, vascular and glial compartments is what contributes to an unhealthy environment and ultimately to neurodegeneration. It is difficult to say with certainty which process is the most important deleterious event, and which is secondary in AD. Good luck with your work.

Thank you for the comment. Would you consider Lipoloysaccharide administration a good experimental model for AD, if not do you suggest a suitable alternative?

INOS is increased in inflammation. free radicals such as iNOS and others released by lipopolysacharide lead to brain damage and an increase in amyloid-beta thus causing Alzheimer's. nNOS is a neuronal neurotransmitter essential for memory. With brain damage or Alzheimer's disease its levels are low. hope this helps to explain your conundrum.

Hello,

I think a small animal model of AD should reproduce as much as possible the AD neuropathology (amyloid-beta plaques and neurofibrillary tangles), and the cerebrovascular and cognitive impairments. There is not perfect model, as far as I know; the transgenic mouse models for example lack overt neurodegeneration, and most lack the tangle pathology (except for the triple transgenic and now 5x transgenic model, but I have not looked into this latest model). You might find the references below useful, and there must be more recent ones. I am not familiar with the features of the LPS model, but it may be useful depending on your specific research questions and as long as any limitations of the model are acknowledged.

Dodart J-C, May P (2005) Overview on rodent models of Alzheimer’s disease. Curr Protoc Neurosci. Chapter 9: Unit 9.22.

Janus C, Chishti MA, Westaway D (2000) Transgenic mouse models of Alzheimer’s disease. Biochim Biophys Acta 1502: 63-75.

Thank you very much for the comments

Both eNOS and iNOS are upregulated in the hippocampus of mice after exposure to traffic related air pollution (which can also lead to neuroinflammation and neuropathology)

(see Bos et al. 2012 Changed gene expression in brains of mice exposed to traffic in a highway tunnel. Inhalation Toxicology, 2012; 24(10): 676–686).

Meanwhile we've also found that expression of the nNOS gene follows the same pattern as iNOS and eNOS (unpublished data).

Hola,buenas tardes.Mas que un comentario quisiera preguntar,si tienen experiencia clínica en el uso de oxido nítrico en pacientes con demencia(mixta,vascular,alzheimer).Yo lo estoy usando desde hace dos meses en mis pacientes(soy Psiquiatra),como alternativa,en lugar de usar nimodipina,citicolina.

It has been reported that many cerebral vessels show p53-associated apoptosis relative to brains with uncomplicated apoptosis. Nitric Oxide synthase III gene had also been reported to show altered expression in alzheimer's disease and cardiovascular complications and reduced NOS-III expression in cerebral vessels is associated with vascular smooth muscle apoptosis and beta-amyloid plaques.

In a recent experiment from our lab we  gained evidence that both iNOS and nNOs are involved in the induction of lipopolysaccharide - model of Alzheimer's disease. We also can provide evidence that systemic inflammation is a predisposing factor in induction of this model of Alzheimer's disease .

I am sending to your attention updated information on the matter.

Telomere Length Shortening and Alzheimer Disease—A Mendelian Randomization StudyYiqiang Zhan, MD1; Ci Song, PhD1; Robert Karlsson, PhD1; Annika Tillander, PhD1; Chandra A. Reynolds, PhD2; Nancy L. Pedersen, PhD1; Sara Hägg, PhD1

[+-] Author Affiliations 1Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

2Department of Psychology, University of California, Riverside

JAMA Neurol. 2015;72(10):1202-1203. doi:10.1001/jamaneurol.2015.1513.

Thank you Dr Marianne for your attention

nitric oxide metabolites (NOx) altered in brain although with western diet (induction metabolic syndrome, MS) in rat (40% calorie from fat), as NOx content decreased in hippocampus and increased in the other parts of the brain associated with increased oxidative stress (malondehyldehyde, MDA) in brain and serum in MS experiment model (this data presentation in congress but still not been published) .