According to a very recent study conducted at Duke University, Alzheimer’s disease(AD) results from altered brain immune response disturbances. This idea is not new. Other scientists have increasingly offered evidence showing that immunity loss may play a causal role in AD.
However, what is new is the finding that immunity decline in the brain is due to dwindling supplies of the vital nutrient arginine, an amino acid. What is also new is the finding that in AD, immune cells that normally protect the brain instead begin to consume arginine.
What is new is the finding that
immunity decline in the brain is due
to dwindling supplies of arginine.
Blocking Arginine’s Decline in the Brain
When the researchers used a small-molecule drug to block the decline of arginine in a special AD prone breed of mice (called CVN-AD mice), the principle characteristics of Alzheimer’s disease dissipated — i.e., plaques and tangles were reduced. The study not only points to a new potential cause of Alzheimer’s, but also may lead to a new treatment strategy — or the reconsideration of an old therapy (more on this later).
Is Suppression of Brain Immunity Related to AD?
A few prior studies suggest that along with increased expression of proinflammatory mediators in AD, the inflammatory locale in the brain may also include immunosuppressive components. This immunosuppressive bias is consistent with the brain’s status as an immune privileged site. This means that it is able to tolerate the introduction of antigens (antibody generators) without producing inflammatory immune responses. Nonetheless, the contribution of immunosuppression to neuronal cell loss and other AD pathology has remained largely unexplored.
Lower Nitric Oxide Levels Increase Alzheimer’s
The Duke paper suggests that when immune-mediated nitric oxide (made from arginine) is lowered to mimic human levels, the fundamental features of AD — amyloid deposition, hyper-phosphorylated and aggregated tau, behavioral changes, and age-dependent hippocampal neuronal loss — become more evident. This makes sense, given our knowledge about the value of nitric oxide in maintaining healthy blood vessels in the body as well as the brain.
“If indeed arginine consumption [destruction] is so important to the disease process, maybe we could block it [the consumption mechanism] and reverse the disease,” said Carol Colton in a press release. Dr. Colton is the senior author of the new paper and professor of neurology at the Duke University School of Medicine. Yet this new idea of reversing AD is far flung, given the research that must still be done in other animal studies and in humans, not to mention the lengthy (over 10 years) and very costly process (more than $1 billion) to meet the FDA’s requirements.
The Duke study may represent new
ground by revealing that specific
immune cells and degradation of
arginine might be linked to
Alzheimer’s disease development.
Degradation of Arginine Inhibits Brain Immunity
As explained in the study, in accord with the model used, when AD develops, certain immune cells called microglia, which normally protect the brain, instead start a pattern of activity that inhibits the immune system. The Duke study may represent new ground by revealing that specific immune cells and degradation of arginine might be linked to Alzheimer’s disease development. The researchers observed that in AD, immune cells that normally protect the brain instead begin to consume the vital nutrient arginine.
Mice Designed to Possess Immune System Similarity
To explore their hypotheses, the researchers used a specific mouse model (CVN-AD), an engineered species designed to have an immune system more similar to that found in humans. The CVN-AD mouse model can develop features of human-like AD, namely plaques and tangles in the brain, neuronal loss and behavior changes. However, CVN-AD mice have only recently been used in research, starting in 2013 by Dr. Colton and her team. CVN-AD mice lack inducible nitric oxide synthase (iNOS), making them different than humans. It is interesting to note that one of the reasons galantamine is beneficial for AD is because it inhibits the production of iNOS.
Immune Components the Same Except for Microglia
By searching for immune anomalies throughout the lifespan of CVN-AD mice, the Duke researchers found that the majority of the immune components remain the same, with one exception: microglia. Microglia are a type of brain-resident white blood cell that act as the main immune defense mechanism in the central nervous system (the brain and spinal cord).
Altered Gene Expressions
In CVN-AD mice, microglia were found to divide and change early in the disease course. By analyzing gene activity patterns in microglia cells, the researchers found a higher expression of genes linked to immunosuppression, and a reduced expression of genes that stimulate the immune system.
“It’s surprising, because [suppression of the immune system is] not what the field has been thinking is happening in Alzheimer’s disease,” said the study’s first author Matthew Kan in the Duke press release. The general idea is that the brain releases molecules that boost the immune system, potentially leading to brain tissue damage.
From studying changes in brain immunity in relation to neuronal loss, and contrary to the predominant view that AD pathology is driven by proinflammatory factors, the researchers found that the pathology in CVN-AD mice is caused by local immune suppression.
Microglia and Arginase Result in Arginine Breakdown
Some hippocampal neuronal death was associated with the presence of immunosuppressive microglia and extracellular arginase, resulting in arginine catabolism and reduced levels of total brain arginine.
Pharmacologic disruption of the arginine utilization pathway by an inhibitor of arginase and ornithine decarboxylase protected the mice from AD-like pathology and significantly decreased microglia expression. The findings strongly implicate local immune-mediated amino acid catabolism as a novel and potentially critical mechanism mediating the age-dependent and regional loss of neurons in humans with AD.
Arginase: An Enzyme that Breaks Down Arginine
Before the mice began showing AD, the Colton team blocked arginase, an enzyme that breaks down arginine, using the drug difluoromethylornithine, also known as DFMO. As a result, the scientists saw fewer microglia and plaques develop in the brains of the mice, and the mice performed better on memory tests. DFMO has been used for cancer therapy with mixed results. High doses for prolonged periods cause diarrhea, abdominal pain, and emesis, as well as moderate anemia, leukopenia, and thrombocytopenia. These serious side effects brought early cancer treatment usage to a halt.
Does the study suggest that people should eat more arginine or take dietary supplements?
According to the press release, but not the study, the answer is ‘no,’ Colton said, partly because a dense mesh of cells and blood vessels called the blood-brain barrier determines how much arginine will enter the brain. While this may be so, it is only conditionally true that eating more arginine may not help more get into the sites of the brain that need it. Besides, if the scientists’ theory is correct, then the enzyme arginase, unless it’s blocked, would still break down the arginine. No evidence is offered for this.
Oral arginine supplementation has been used in various studies to improve endothelium-dependent nitric oxide-mediated vasodilation. It is worth noting that the amino acid citrulline is more readily absorbed and at least in part converted to arginine — so it too, may play a role in supplying more arginine to the brain.
Analysis of gene activity
patterns in microglia, found a higher
expression of genes linked to
immunosuppression and a reduced
expression of genes that stimulate
the immune system.
In a recent issue of Life Extension News, Durk Pearson & Sandy Shaw wrote that there has been considerable research on nitric oxide synthase because of the importance of nitric oxide in functions such as vasodilation, in the body and in the brain. They go on to report that an inadequate supply of arginine, or too little of the cofactor tetrahydrobiopterin (BH4), (which can be mimicked by folic acid), can uncouple nitric oxide synthase from the production of nitric oxide, producing a bunch of free radicals.
Colton and colleagues also report that an increase in the arginase pathway can inhibit arginine production of nitric oxide. Among the causes of this increase in arginase rerouting are reperfusion injury, asthma, psoriasis, arthritis, and male and female cancers. The increased arginase decreases arginine’s availability to be converted to nitric oxide, as well as increasing ornithine, which can be converted to polyamines and procellular proliferation factors.
Arginase in the Brain
According to Durk & Sandy (see “The Arginine Metabolic Pathways: Nitric Oxide Synthase and Arginase” in the April 2004 issue), “Not only is arginine in the brain vital for the manufacture of nitric oxide, it is also used in brain protein synthesis and is the substrate for the production of urea (detoxification of ammonia), along with other important products.
Decreasing Arginase in the Brain
In the same article Durk & Sandy cite a rat study, “small doses” of caffeine were shown to decrease arginase activity in the brain. The results indicated that caffeine’s inhibitory effect on arginase left more arginine available for use by the nitric oxide synthase pathway.
As the authors explained, caffeine is an inhibitor of adenosine receptors, decreasing adenosine bound to its receptors and increasing free adenosine. Adenosine, adenine, inosine, and uric acid are competitive inhibitors of arginase. Valine, leucine, isoleucine, and ornithine are also reported to have inhibitory effects on arginase activity.
Caffeine and compounds related to caffeine, such as theophylline and theobromine, increase cellular levels of cyclic AMP that are hypothesized to possibly be, at least in part, a reason for caffeine’s depression of arginase activity. Durk & Sandy wonder too, whether the prescription drug pentoxifylline, a prescription methylxanthine drug used in the treatment of poor circulation in the extremities (especially legs), might reduce arginase activity (thus increasing arginine’s availability to be converted to nitric oxide), which (if true) might account for some of the drug’s beneficial effects.
Local Immune Mediated Amino Acid Catabolism Implicated
The Colton et al study
concludes that arginase reduces
arginine in the brain of their mouse
model, decreasing the beneficial
effects of nitric oxide.
The Colton et al study concludes that arginase reduces arginine in the brain of their mouse model, decreasing the beneficial effects of nitric oxide. Also they find that a drug can inhibit the activity of arginase, thereby protecting the mice from AD-like pathology. Quoting the paper, “Our findings strongly implicate local immune mediated amino acid catabolism as a novel and potentially critical mechanism mediating the age-dependent and regional loss of neurons in humans with AD.”
Arginine Improves Brain Function
We have already voiced our opinions about the supposed “uselessness” of arginine (and citrulline) to help solve this problem in accordance with the researchers hypothesis. Even though it seems reasonable it is certainly not the final word. And we have our doubts about the safety of the drug that they proffer.
Furthermore, among the large amount of literature indicating that arginine may be helpful for dementia is a clinical studyshowing that arginine has been found to be effective in reducing lipid peroxidation and increasing cognitive function (see Fig. 2).
In this study, 16 elderly people with cardiovascular disease (mean age, 79 years), who had been living in a nursing home for 2 to 4 years, were treated with relatively low doses of oral arginine (1.6 g/day) for 3 months. Their cognitive function was evaluated using the Hasegawa Dementia Scale (HDS-R) before treatment started, after 3 months of treatment, and finally 3 months after treatment stopped. The HDS-R is a widely used measure in Japan. A score of 30 on the HDS-R is considered normal, while a score of 20 or lower indicates dementia.
After 3 months of treatment with arginine, cognitive function improved significantly in all subjects from a mean of 16 to 23. Within 3 months of stopping arginine treatment, the HDS score returned to pretreatment levels (17) (Fig. 1). Lipid peroxide levels (an indicator of oxidative stress) also declined significantly during arginine treatment compared with the baseline and post-treatment measurements. The authors hypothesized that arginine treatment improved cognitive function by increasing nitric oxide levels, by reducing oxidative stress, or both.
There are many good reasons to keep our blood pressure under control; reducing the risk of heart attack, stroke and kidney failure are the most commonly mentioned. Now we know that blood pressure control with arginine may also help preserve our cognitive function.
Synergy Worldwide has the number one clinically tested Arginine supplement on the market and their standards of safety, purity and potency is accredited by the NCF. They perform over 600 plus to ensure this high standard and their products are higher than pharmaceutical grade and beyond organic in terms of contaminants as the are tested to parts per trillion, which is unheard of in the industry.
Can Brain Arginine
Reduce Alzheimer’s? By Will Block
- Kan MJ, Lee JE, Wilson JG, et al. Arginine deprivation and immune suppression in a mouse model of Alzheimer’s disease J. Neurosci. 2015;35(15):5969 – 82.
- A New Potential Cause for Alzheimer’s: Arginine Deprivation. Duke Today. April 14, 2015. https://today.duke.edu/2015/04/arginine. Accessed April 15, 2015.
- Hoos MD, Richardson BM, Foster MW, Everhart A, Thompson JW, Moseley MA, Colton CA. Longitudinal study of differential protein expression in an Alzheimer’s mouse model lacking inducible nitric oxide synthase. J Proteome Res. 2013 Oct 4;12(10):4462 – 77.
- Tsvetkova D, Obreshkova D, Zheleva-Dimitrova D, Saso L. Antioxidant activity of galantamine and some of its derivatives. Curr Med Chem. 2013;20(36):4595 – 608.
- Schwedhelm E, Maas R, Freese R, et al. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. Br J Clin Pharmacol. 2008 Jan;65(1):51 – 9.
- Nikolic J, Bjelakovic G, Stojanovic I. Effect of caffeine on metabolism of L-arginine in the brain. Mol Cell Biochem. 2003 Feb;244(1 – 2):125 – 8.
- Ohtsuka Y, Nakaya J. Effect of oral administration of L-arginine on senile dementia. Am J Med. 2000;108:439.