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Could Sugar Found in Milk Contribute to Alzheimer's?
Serenoa
Posted: Tuesday, December 13, 2016 5:33 AM
Joined: 4/24/2012
Posts: 484


Could milk cause Alzheimer's? Aparently a sugar (galactose) in milk may contribute to neurodegeneration. There seems to be a connection to oxidative dammage and inflamation from galactose consumption. D-galactose (in combination with other things) is commonly used to induce neurodegenerative conditions in mice in order to study various therapies. Here's two pieces of evidence:

Could Lactose Explain the Milk & Parkinson’s Disease Link?

 http://nutritionfacts.org/video/could-lactose-explain-the-milk-and-parkinsons-disease-link/

 

Altered expression of Abeta metabolism-associated molecules from d-galactose/AlCl3 induced mouse brain

http://www.sciencedirect.com/science/article/pii/S0047637408002844


Serenoa
Posted: Wednesday, December 14, 2016 5:36 AM
Joined: 4/24/2012
Posts: 484


Galactose (found mostly in the lactose sugar of milk) seems to have beneficial effects in many regards including the development of the immune system. However, it may also contribute to aging. Perhaps it follows the old wisdom of milk being for babies. In other words too much lactose over time may over activate the immune system causing inflammation.

 

Gene Transcriptional and Metabolic Profile Changes in Mimetic Aging Mice Induced by D-Galactose

"D-galactose injection has been shown to induce many changes in mice that represent accelerated aging."

https://www.ncbi.nlm.nih.gov/pubmed/26176541


Lane Simonian
Posted: Wednesday, December 14, 2016 10:43 AM
Joined: 12/12/2011
Posts: 4998


Not directly, but here is another hint:

Inducible Nitric Oxide Synthase is Critical to Peroxynitrite/Nitrotyrosine Formation in a Galactose Induced Model of Diabetic Retinopathy

http://iovs.arvojournals.org/article.aspx?articleid=2418619


Serenoa
Posted: Wednesday, December 14, 2016 5:16 PM
Joined: 4/24/2012
Posts: 484


Interesting. So this study is confirming that the sugar galactose is an immune system stimulator. It promotes NADH oxidase which creates reactive oxygen species (ROS). Omaga 6 fatty acids, which are well known to be inflammatory, also activate NADH oxidase. From your above article Lane:

"Increased levels of NADH oxidase was observed in retinas of all mice fed the galactose diet"

 Then from Wikipedia:

 NAD(P)H oxidase is a membrane-associated enzyme that catalyzes the production of superoxide– a reactive free radical– "

  


Lane Simonian
Posted: Thursday, December 15, 2016 12:36 AM
Joined: 12/12/2011
Posts: 4998


Good information.  The combination of NADPH oxidase and inducible nitric oxide synthase is what lead to the death of neurons (superoxide + inducible nitric oxide=peroxynitrite).

Mechanism of inflammatory neurodegeneration: INOS and NADPH oxidase

Activation of PHOX (phagocytic NADPH oxidase) alone causes no death, but when combined with expressed iNOS results in extensive neuronal death via peroxynitrite production.

Serenoa
Posted: Friday, December 16, 2016 4:57 AM
Joined: 4/24/2012
Posts: 484


Thanks Lane. So, it's only when iNOS is activated that inflammation becomes a problem. I have been reviewing iNOS. It seems to vary from the other two NOSs in that it is activated by infectious agents and various cytokines and causes immune cell to produce massive amounts of NO. And, NO can be good or bad. When produced in large quantity (and maybe in certain tissues) it causes dammage. This is where peroxynitrite comes in right?
Lane Simonian
Posted: Friday, December 16, 2016 10:45 AM
Joined: 12/12/2011
Posts: 4998


This is it, Serenoa.  Nitric oxide by itself is positive in part because it contributes to adequate blood flow.  But when it combines with superoxide anions, it forms peroxynitrite which limits the availability of nitric oxide (in part because the nitric oxide combines with superoxide anions and in part because peroxynitrite oxidizes one of the co-factors for nitric oxide production--BH4).  The blood flow in the brain becomes restricted.  

Cerebral blood flow regulation by nitric oxide in neurological disorders.

 

https://www.ncbi.nlm.nih.gov/pubmed/19767882


And immune cells produce inducible nitric oxide that lead to the formation of peroxynitrite that damage cell tissue that can lead to further inflammation (although peroxynitrite can also damage immune cells).  

Implications of glial nitric oxide in neurodegenerative diseases

 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538301/

 

This I think is the connection between various chronic bacterial, viral, and fungal infections and Alzheimer's disease.  These infections increase the production of peroxynitrite.  Peroxynitrite can kill the pathogen but it can also kill brain cells.

In mice at least, if you knockout the inducible nitric oxide synthase gene you basically knockout Alzheimer's-like disease.

https://www.ncbi.nlm.nih.gov/pubmed/16260491

 

 


Lane Simonian
Posted: Saturday, December 17, 2016 9:58 AM
Joined: 12/12/2011
Posts: 4998


I am looking for the pathways that lead to microglia activation and subsequent inflammation in Alzheimer's disease.  Here are some interesting ones that I have found so far.

Closely aligned with Wnt1 and Akt1 are the integrated canonical pathways of synthase kinase-3Beta (GSK-3beta) and Beta-catenin. Through Akt1 dependent pathways, Wnt1 phosphorylates GSK-3Beta and maintains Beta-catenin integrity to insure its translocation from the cytoplasm to the nucleus to block apoptosis. Our work outlines a highly novel role for Wnt1 and its integration with Akt1, GSK-3Beta, and Beta-catenin to foster neuronal cell survival and repress inflammatory microglial activation that can identify new avenues of therapy against neurodegenerative disorders.

 Peroxynitrite induces inactivation of the Akt pathway

This one indicates that there are many pathways by which microglia are activated.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3741576/

One way in which microglia increase inflammation is via peroxynitrite which activates COX-2

COX-2 and Alzheimer's disease: potential roles in inflammation and neurodegeneration.

 

The role of peroxynitrite in cyclooxygenase-2 expression of rheumatoid synovium.

Reactive oxygen intermediates play an important role in the inflammatory processes of rheumatoid arthritis. Cyclooxygenase-2 is an inducible form of an enzyme involved in prostanoid biosynthesis. This study linked peroxynitrite (ONOO-) to the signaling pathways that induce COX-2.


Lane Simonian
Posted: Saturday, December 17, 2016 10:25 AM
Joined: 12/12/2011
Posts: 4998


This was an interesting finding regarding microglia in Alzheimer's disease:

Dr. Grietje Krabbe of the laboratory of Professor Helmut Kettenmann (MDC) and Dr. Annett Halle of the Neuropathology Department of the Charité headed by Professor Frank Heppner demonstrated that the microglial cells around the deposits do not show the classical activation pattern in mouse models of Alzheimer´s disease. On the contrary, in the course of the Alzheimer’s disease they lose two of their biological functions. Both their ability to remove cell fragments or harmful structures and their directed process motility towards acute lesions are impaired. The impact of the latter loss-of-function needs further investigation.

Peroxynitrite may harm microglia as they do other cells.

Nitric oxide (NO) and its derivatives peroxynitrite and S-nitrosothiols inhibit mitochondrial respiration by various means, but the mechanisms and/or the reversibility of such inhibitions are not clear. We find that the NO-induced inhibition of respiration in isolated mitochondria due to inhibition of cytochrome oxidase is acutely reversible by light. Light also acutely reversed the inhibition of respiration within iNOS-expressing macrophages, and this reversal was partly due to light-induced breakdown of NO, and partly due to reversal of the NO-induced inhibition of cytochrome oxidase.

Microglia dependent inflammation may be decreased in Alzheimer's disease, but microglia independent inflammation likely continues, so Alzheimer's disease may be a partially neuroinflammatory disease.

While microglia are not solely responsible for the inflammatory or immune mediated responses in the brain, they are poised to be able to rapidly respond to environmental changes. The presence of activated microglia within injured brain regions and in post-mortem tissue from patients with various neurodegenerative diseases, has led to the initial assumption that all reactive microglia would contribute to an adverse and degenerative process. However, this makes the assumption that somehow, a brain resident glial cell can be transformed into an aggressive effector cell that can attack healthy neurons either physically, as by phagocytosis, or via secreted factors. However, in the mature brain, microglia seem to alter their morphology dependent upon the specific task at hand. Such resident immune responders may be beneficial in the healing phases of CNS injury by actively monitoring and controlling the extracellular environment, walling off areas of the CNS from non-CNS tissue, and removing dead, damaged, or dysfunctional cells. Microglia can upregulate a variety of surface receptors and produce multiple secreted factors including pro- and anti-inflammatory cytokines, nitric oxide, reactive oxygen species (ROS), glutamate, and growth factors. However, microglia also express the glutamate transporter, GLT-1 and, thus, may provide a level of protection through the elimination of extracellular glutamate []. In addition, microglia can facilitate the apoptosis and phagocytosis of infiltrating T cells through various signaling pathways leading to a subsequent down regulation of microglial immune activation []. This plethora of responses is representative of the dichotomy of microglia reactivity in promoting neuronal survival or degeneration.

Peroxynitrite may reduce one form of inflammation--that resulting from microglia activation, but also remove some of its more positive functions (such as the transport of extracellular glutamate).



Lane Simonian
Posted: Saturday, December 17, 2016 6:05 PM
Joined: 12/12/2011
Posts: 4998


I think this is as close as I can get to clarity regarding microglia activation and Alzheimer's disease.

However, in chronic neurodegenerative diseases such as Alzheimer's disease where in vivo analyses are critical to understanding the long-term disease processes, our knowledge of the integrated tissue immune response and the outcome of this immune activity to neurons and other glia over the extended course of disease is more limited. This is due in part to the complexity of microglial activation states and to the location of microglia in a dense neuronal network. Classical activation, alternative activation and acquired deactivation are each found in the brain during chronic neuroinflammatory diseases and may demonstrate regional differences in expression levels. This review will identify "markers" that can be used to explore inflammatory states in the brain and will discuss the likely functional outcomes when these cytoactive factors are expressed. A broad-based functional view is provided that is designed to more fully explore the balance between inflammo-toxic and inflammo-resolution factors that govern chronic disease progression.

Activated microglia may play an more important role in neuronal cell death early in Alzheimer's disease and less of a role later in Alzheimer's disease.  Ironically, the formation of peroxynitrite via microglia may downregulate microglia as the disease progresses.  And yet, peroxynitrite can also elicit an immune response via other mechanisms.  This one is for t lympocytes but it probably also applies to microglia:

We also provide evidence indicating that peroxynitrite is produced during in vitro immune activation, mainly by cells of the monocyte/macrophage lineage. Furthermore, immunohistochemical studies demonstrate the in vivo generation of nitrating species in human lymph nodes undergoing mild to strong immune activation. Our results point to a physiological role for ONOO- as a down-modulator of immune responses and also as key mediator in cellular and tissue injury associated with chronic activation of the immune system.


Serenoa
Posted: Sunday, December 18, 2016 6:50 AM
Joined: 4/24/2012
Posts: 484


Lane, I had to go back and relearn what I had forgotten about nitric oxide (NO). NO is facinating! Let me leave microglia alone for now and hit you with more NO related info. I am now getting the connections and critical importance of NO in relation to oxidative stress which you have writen about so much Lane. This quote sums it up well:

"Increased ROS concentrations reduce the amount of bioactive NO by chemical inactivation to form toxic peroxynitrite. Peroxynitrite-in turn-can "uncouple" endothelial NO synthase to become a dysfunctional superoxide-generating enzyme that contributes to vascular oxidative stress." "An enhanced inactivation and/or reduced synthesis of NO is seen in conjunction with risk factors for cardiovascular disease."

Basically, a deficiency of NO, by whatever means, leads to disease. Another factor relating to NO is the glutamate-NO-cGMP pathway. I don't fully understand this yet, but I know you Lane have many times mentioned NMDA receptors, and I can see that this may be very relevant to Alzheimer's:

"A main pathway mediating modulation of learning by NMDA receptors is the glutamate-nitric oxide (NO)-cyclic GMP (cGMP) pathway. Activation of NMDA receptors increases calcium which binds to calmodulin and activates neuronal nitric oxide synthase (NOS). This increases NO, which activates soluble guanylate cyclase, increasing cGMP."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5025658/


Lane Simonian
Posted: Sunday, December 18, 2016 9:51 AM
Joined: 12/12/2011
Posts: 4998


I am happy to put microglia aside at least for the moment since there is a lot of ambiguity as to the role it may play in Alzheimer's disease.  Some scientist want to try to upregulate them to remove amyloid plaques; other scientists want to downregulate them to reduce inflammation.  My feeling is just leave them alone.

The key in any case is likely nitric oxide.  I forgot that when peroxynitrite oxidates BH4 you not only produce less nitric oxide, you produce more superoxide anions. And both more inducible nitric oxide and superoxide anions continue to be produced via the following pathway (NMDA receptor overactivation--calcium influx--neuronal nitric oxide synthase--p38 Mapk--NADPH oxidase and inducible nitric oxide synathase--superoxide anions and inducible nitric oxide--peroxynitrite--caspase 3--the death of neurons via energy deprivation).  I had never heard of BH4 until Tome(ek) brought it up on these boards several years ago.  It was a much bigger lead that I realized at the time.

In cases of low oxidative stress, part of this pathway can lead to the activation of the phosphatidylinositol 3-kinase/Akt pathway which is needed for the production of endothelial nitric oxide (the good NO).  

Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation


Under high levels of oxidative stress though this pathway is cut off.

Peroxynitrite induces inactivation of the Akt pathway.


Paradoxically, peroxynitrite by contributing to limited blood flow (by reducing endothelial nitric oxide), by contributing to tissue damage, or in some cases cell growth can lead to a variety of diseases ranging from Alzheimer's diseases, to various inflammatory and auto-immune disease, and to cancer.

 2007 Jan;87(1):315-424.

Nitric oxide and peroxynitrite in health and disease.

Abstract

The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.


I could be wrong around the edges, but in my view this is the holy grail for the treatment of many disease that are currently either poorly treated or not treated at all.


Lane Simonian
Posted: Sunday, December 18, 2016 9:59 AM
Joined: 12/12/2011
Posts: 4998


This one helps to fill in some remaining blanks:

 2002 Apr;81(2):218-28.

Akt pathway mediates a cGMP-dependent survival role of nitric oxide in cerebellar granule neurones.

Abstract

Apoptotic death results from disrupting the balance between anti-apoptotic and pro-apoptotic cellular signals. The inter- and intracellular messenger nitric oxide is known to mediate either death or survival of neurones. In the present work, cerebellar granule cells were used as a model to assess the survival role of nitric oxide and to find novel signal transduction pathways related to this role. It is reported that sustained inhibition of nitric oxide production induces apoptosis in differentiated cerebellar granule neurones and that compounds that slowly release nitric oxide significantly revert this effect. Neuronal death was also reverted by a caspase-3-like inhibitor and by a cyclic GMP analogue, thus suggesting that nitric oxide-induced activation of guanylate cyclase is essential for the survival of these neurones. We also report that the Akt/GSK-3 kinase system is a transduction pathway related to the survival action of nitric oxide, as apoptosis caused by nitric oxide deprivation is accompanied by down-regulation of this, but not of other, kinase systems. Conversely, treatments able to rescue neurones from apoptosis also counteracted this down-regulation. Furthermore, in transfection experiments, overexpression of the Akt gene significantly decreased nitric oxide deprivation-related apoptosis. These results are the first evidence for a mechanism where endogenous nitric oxide promotes neuronal survival via Akt/GSK-3 pathway.


Larrytherunner
Posted: Monday, December 19, 2016 1:47 PM
Joined: 2/26/2016
Posts: 243


According to Wikipedia, lactose in food (such as dairy products) is broken down by the enzyme lactase into glucose and galactose. Galactose is converted into glucose by the action of three enzymes, known as the Leloir pathway. A person who lacks one of these enzymes has galactosemia, which is a serious and often fatal genetic disease. It is also quite rare, with an occurrence of 1 in 60,000 births of European ancestry. In the US, infants are tested for the disease at birth. 

Galactose metabolism was discovered as the cause of the disease in 1956, and galactose has been known to cause organ and brain injury for more than 50 years.

I would be interested in knowing if in people who do not have galactosemia, it is possible for galactose to leak from the gut to the blood stream. A clinical trial could be done with a large group,  perhaps composed of people over 55, with and without Alzheimer's, and test for galactose in the blood. Perhaps it can answer the question "Can galactose get into the blood and reach the brain of people who do not have galactosemia". Meanwhile if a person wants to avoid galactose, he or she can choose to eat lactose-free dairy products.

https://en.m.wikipedia.org/wiki/Galactosemia

Iris L.
Posted: Monday, December 19, 2016 3:23 PM
Joined: 12/15/2011
Posts: 17544


I drink two glasses of non-fat skim milk a day.  My diagnosis is cognitive impairment not otherwise specified (possibly due to lupus, antiphospholipd syndrome, or chronic fatigue syndrome, or even something else).  No beta-amyloid plaques were found on my Amyvid PET scan.  I don't have lactose intolerance.  Is it okay for me to continue drinking milk at my age, 66 years?  


Iris L.


Serenoa
Posted: Monday, December 19, 2016 5:21 PM
Joined: 4/24/2012
Posts: 484


Well, I would say the research is not conclusive. In these situations I like to take a step back and consult my common sense. First of all today's milk is full of hormones, pesticides, and inflammatory omega-6s, no doubt about that. Second, sugar dammages the body and milk has sugar in it. Third, milk is great for baby cows, but adult humans only recently (ca. 10,000yrs ago) started consuming it. Fourth, you don't need that much calcium. Personally I try to stick to organic, grass-fed cheese, and half and half (coffee). Don't be afraid of the fat. This is just my opinion. I'm not a doctor.
Larrytherunner
Posted: Tuesday, December 20, 2016 9:28 AM
Joined: 2/26/2016
Posts: 243


Iris, I found a study of milk and dairy consumption and the risk of dementia in an elderly Japanese population. The study, published in 2014, had a 17 year follow up and included 1,081 participants. Their conclusion was that greater milk and diary intake reduced the risk of dementia, especially AD, in the population.

So my advice is to forget about this discussion, which is filled with all kinds of assumptions, and continue to drink milk. It is probably good for you.

https://www.ncbi.nlm.nih.gov/pubmed/24916840


Lane Simonian
Posted: Tuesday, December 20, 2016 10:59 AM
Joined: 12/12/2011
Posts: 4998


I hesitate to post as I have no advice one way or another, Iris.  Milk contains components that are both good and bad for the brain--so the studies on whether milk is good or bad for the brain are all over the place.



Iris L.
Posted: Wednesday, December 21, 2016 3:39 PM
Joined: 12/15/2011
Posts: 17544


Thanks, everyone, for the responses.  I see that there are pros and cons.  After 66 years of drinking milk, I think I will continue.  


Iris L.


Serenoa
Posted: Wednesday, December 21, 2016 6:05 PM
Joined: 4/24/2012
Posts: 484


Ok Lane, I'm in over my head again. But I like your connection of NO and PI3k/Akt pathway, this is very interesting. Here's another one:

Activation of the Phosphatidylinositol 3-Kinase/Protein Kinase Akt Pathway Mediates Nitric Oxide-Induced Endothelial Cell Migration and Angiogenesis

http://mcb.asm.org/content/23/16/5726.short

 

Then I ran across this odd piece of research:

Jujube promotes learning and memory in a rat model by increasing estrogen levels in the blood and nitric oxide and acetylcholine levels in the brain

https://www.spandidos-publications.com/10.3892/etm.2013.1063

Hmmmm.... 


Lane Simonian
Posted: Wednesday, December 21, 2016 6:57 PM
Joined: 12/12/2011
Posts: 4998


In that estrogen acts through a g protein coupled receptor(s) to improve memory and learning via NMDA receptor and subsequent Akt activation this would make sense.  

Acetylcholine Mediates the Estrogen-Induced Increase in NMDA Receptor Binding in CA1 of the Hippocampus and the Associated Improvement in Working Memory

Effects of estrogen on acetylcholine release in frontal cortex of female rats: involvement of serotonergic neuronal systems.

Both seretonin and acetylcholine receptors are g protein-coupled receptors.  The overactivation and then deactivation of most g protein-coupled receptors (due to nitro-oxidative stress) partially explains the loss of smell, distrubed sleep, inability to retrieve short-term memory, decreased alertness, and declining social recognition in Alzheimer's disease (all of which depend upon functioning g protein-coupled receptors).

This study on jujube tea may be more relevant to Alzheimer's disease:

The “Oxygen Paradox” is that higher eukaryotic aerobic organisms cannot exist without
oxygen, yet oxygen is inherently dangerous to their existence. Moreover, reactive oxygen species (O2-, H2O2, *OH) and peroxynitrite (ONOO-) are proposed as agents attacking fatty acids in cells, tissues, or organism, giving rise to an oxidative damage of biologically important molecules. Especially, ONOO- formed from superoxide (O2-) and nitric oxide (NO) acts as a strong cytotoxicant giving carcinogenisis, cell death and low density lipoprotein oxidation. In the present study, 21 kinds of teas including cereal teas (job's tears tea, roasted barley tea, roasted indian corn tea, scorched rice tea), fruit teas (boxthorn tea, chinese quince tea, citron tea, dried persimmon tea, jujube teaky?lmy?ngja tea, sansuyoo tea), leaf teas (black tea, duch’ung tea, green tea, oolong tea, persimmon leaf tea) and root teas (arrowroot tea, chicory tea, ginger tea, ginsengtea, solomon's seal tea) were screened for the scavenging activities against peroxynitrite formation by SIN-1 and peroxynitrite itself. Green tea showed the strongest peroxynitrite scavenging activity. Moreover, 21 kinds of teas including cereal teas, fruit teas, leaf teas and root teas were screened for the scavenging effects against total free radical formation by using DCFDA assay. Among the several teas, green tea showed the strongest scavenging activity respectively. These results suggest that green tea might show cytoprotective action through antioxidant and peroxynitrite scavenging activity.

Peroxynitrite scavengers not only lower levels of peroxynitrite, they partially reverse the oxidation (damage) to receptors needed for the retrieval of short-term memory, smell, sleep, balanced mood, alertness, and social recognition.  By de-nitrating the phosphatidyinositol 3-kinase they allow for more blood flow in the brain and for the regeneration of neurons in the brain.  They also limit the death of neurons.




Lane Simonian
Posted: Wednesday, December 21, 2016 7:06 PM
Joined: 12/12/2011
Posts: 4998


There may be an additional point here: a number of drug companies are focusing on acetylcholine and serotonin receptor agonists to improve memory in Alzheimer's disease, but it does not seem like this approach will work because these receptors are already damaged by oxidation.  It would be like trying to stick a key into a lock that is jammed--it won't work unless the lock is unjammed.  This as a whole is likely the better approach.

 2002 Sep 20;950(1-2):10-20.

Inactivation of the human brain muscarinic acetylcholine receptor by oxidative damage catalyzed by a low molecular weight endogenous inhibitor from Alzheimer's brain is prevented by pyrophosphate analogs, bioflavonoids and other antioxidants.

Abstract

Oxidative stress has been implicated as a contributing factor to neurodegeneration in Alzheimer's disease. An endogenous, low molecular weight (LMW) inhibitor from Alzheimer's brain inactivates the human brain muscarinic acetylcholine receptor (mAChR). The inhibitor prevents agonist and antagonist binding to the mAChR as assessed by radioligand binding studies. The LMW endogenous inhibitor, which has components with molecular weights between 100 and 1000 Da, requires dissolved oxygen and glutathione. Prevention of inactivation of the mAChR with peroxidase suggests that the LMW endogenous inhibitor generates peroxide. Heme, previously shown to be present in the LMW endogenous inhibitor, also inactivates the mAChR in the presence of peroxide. Free radical damage to the muscarinic receptor by the endogenous inhibitor can be prevented through the use of naturally occurring antioxidants including bilirubin, biliverdin, carnosol, myricetin and quericetin. In addition, pyrophosphate, imidodiphosphate, bisphosphonates and related compounds also protect the muscarinic receptor from free radical damage. Inactivation of the mAChR by the LMW endogenous inhibitor is likely to be a factor in the continual decline of Alzheimer's patients, even those taking acetylcholinesterase inhibitors. Natural antioxidants and pyrophosphate analogs may improve the effectiveness of acetylcholinesterase inhibitors and prove useful in the treatment and prevention of Alzheimer's disease since the muscarinic acetylcholine receptor is required for memory, and decreased cholinergic function is a critical deficit in Alzheimer's disease.


Lane Simonian
Posted: Wednesday, December 21, 2016 7:18 PM
Joined: 12/12/2011
Posts: 4998


Back specifically to jujube:

Alzheimer's disease (AD) is a common neurodegenerative condition that affects the elderly population. Its primary symptom is memory loss. The memory dysfunction in AD has been associated with cortical cholinergic deficiency and loss of cholinergic neurons of the nucleus basalis of Meynert (NBM). Zizyphus jujube (ZJ) activates choline acetyltransferase and may have beneficial effects in AD patients.

Nitro-oxidative stress damages muscarinic acetylcholine receptors, choline acetyltransferase activity and the transport of choline in Alzheimer's disease.  When part of this damage is reversed, a person with Alzheimer's disease can begin retrieving certain types of memory.