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Blocking receptor in brain's immune cells counters Alzheimer's in mice
Myriam
Posted: Thursday, December 11, 2014 1:07 PM
Joined: 12/6/2011
Posts: 3326


The mass die-off of nerve cells in the brains of people with Alzheimer's disease may largely occur because an entirely different class of brain cells, called microglia, begin to fall down on the job, according to a new study by researchers at the Stanford University School of Medicine. 

 

The researchers found that, in mice, blocking the action of a single molecule on the surface of microglia restored the cells' ability to get the job done -- and reversed memory loss and myriad other Alzheimer's-like features in the animals. 

 

The study, to be published online Dec. 8 in the Journal of Clinical Investigation, illustrates the importance of microglia and could lead to new ways of warding off the onset of Alzheimer's disease, which is predicted to afflict 15 million people by mid-century unless some form of cure or prevention is found. The study also may help explain an intriguing association between aspirin and reduced rates of Alzheimer's. 

 

Microglia, which constitute about 10-15 percent of all the cells in the brain, actually resemble immune cells considerably more than they do nerve cells. 

 

"Microglia are the brain's beat cops," said Katrin Andreasson, MD, professor of neurology and neurological sciences and the study's senior author. "Our experiments show that keeping them on the right track counters memory loss and preserves healthy brain physiology." 

 

Implicated: a single molecule 

A microglial cell serves as a front-line sentry, monitoring its surroundings for suspicious activities and materials by probing its local environment. If it spots trouble, it releases substances that recruit other microglia to the scene, said Andreasson. Microglia are tough cops, protecting the brain against invading bacteria and viruses by gobbling them up. They are adept at calming things down, too, clamping down on inflammation if it gets out of hand. They also work as garbage collectors, chewing up dead cells and molecular debris strewn among living cells -- including clusters of a protein called A-beta, notorious for aggregating into gummy deposits called Alzheimer's plaques, the disease's hallmark anatomical feature. 

 

A-beta, produced throughout the body, is as natural as it is ubiquitous. But when it clumps into soluble clusters consisting of a few molecules, it's highly toxic to nerve cells. These clusters are believed to play a substantial role in causing Alzheimer's. 

 

"The microglia are supposed to be, from the get-go, constantly clearing A-beta, as well as keeping a lid on inflammation," Andreasson said. "If they lose their ability to function, things get out of control. A-beta builds up in the brain, inducing toxic inflammation." 

 

The Stanford study provides strong evidence that this deterioration in microglial function is driven, in large part, by the heightened signaling activity of a single molecule that sits on the surface of microglial and nerve cells. Previous work in Andreasson's lab and other labs has shown that this molecule, a receptor protein called EP2, has a strong potential to cause inflammation when activated by binding to a substance called prostaglandin E2, or PGE2. 

 

"We'd previously observed that if we bioengineered mice so their brain cells lacked this receptor, there was a huge reduction in inflammatory activity in the brain," she said. But they didn't know whether nerve cells or microglia were responsible for that inflammatory activity, or what its precise consequences were. So they determined to find out. 

 

Blocking receptor preserves memory 

The experiments began in a dish. Isolating viable microglia from the brain is quite difficult. But it's easy to harvest large numbers of their close cousins, immune cells called macrophages. These cells circulate throughout the body and can be readily obtained from a blood sample. While not carbon copies of one another, microglia and macrophages share numerous genetic, biochemical and behavioral features. 

 

When placed in a dish with soluble A-beta clusters, macrophages drawn from young mice responded calmly, producing recruiting chemicals and not ramping up production of inflammatory molecules. Notably, the output of A-beta-chewing enzymes in these young cells was robust. But macrophages from older mice acted differently: A-beta's presence incited a big increase in EP2 activity in these cells, resulting in amped-up output of inflammatory molecules and reduced generation of recruiting chemicals and A-beta-digesting enzymes. 

 

This early hint that age-related changes in EP2 action in microglia might be promoting some of the neuropathological features implicated in Alzheimer's was borne out in subsequent experiments for which Andreasson's team used mice genetically predisposed to get the mouse equivalent of Alzheimer's, as well as otherwise normal mice into whose brains the scientists injected either A-beta or a control solution. In both groups of mice, the expected deleterious effects on memory and learning didn't arise if EP2 within microglial cells was absent, as a result of a genetic manipulation. Blocking microglial EP2 activity significantly improved these animals' performance on two kinds of standard memory tests: one that assesses how quickly a mouse forgets that it has encountered an object before, and another that rates the mouse's ability to remember where a food reward is in a maze. 

 

Looking beyond aspirin 

Clearly, knocking out EP2 action in A-beta-provoked microglia benefited memory in mice that had either gradually (the "Alzheimer's" mice) or suddenly (the brain-injected mice) acquired excessive A-beta in their brains. Likewise, mouse microglia bioengineered to lack EP2 vastly outperformed unaltered microglia, in A-beta-challenged brains, at such critical tasks as secreting recruiting chemicals and factors beneficial to nerve cells and in producing inflammation-countering, rather than inflammation-spurring, proteins. 

 

Epidemiological reports suggest that the use of nonsteroidal anti-inflammatory drugs, such as aspirin, can prevent the onset of Alzheimer's -- although only if their use is initiated well before any signs of the disorder begin to show up in older people, Andreasson said. "Once you have any whiff of memory loss, these drugs have no effect," she said. NSAIDs' mainly act by blocking two enzymes called COX-1 and COX-2; these enzymes create a molecule that can be converted to several different substances, including PGE2 -- the hormone-like chemical that triggers EP2 action. 

 

Although PGE2 is known to regulate inflammatory changes in the brain, it exercises diverse, useful functions in different tissues throughout the body, from influencing blood pressure to inducing labor. Complicating matters, PGE2 is just one of five different prostaglandins originating from the precursor molecule produced by COX-1 and COX-2. So aspirin and other COX-1- and COX-2-inhibiting drugs may have myriad effects, not all of them beneficial. It may turn out that a compound blocking only EP2 activity on microglial cells, or some downstream consequences within microglial cells, would be better-suited for fending off Alzheimer's without side effects, said Andreasson. Meanwhile, her group is exploring the biological mechanisms via which PE2 signaling pushes microglia over to the dark side. 

 

Journal Reference: 

  1. Jenny U. Johansson, Nathaniel S. Woodling, Qian Wang, Maharshi Panchal, Xibin Liang, Angel Trueba-Saiz, Holden D. Brown, Siddhita D. Mhatre, Taylor Loui, Katrin I. Andreasson. Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models. Journal of Clinical Investigation, 2014; DOI: 10.1172/JCI77487 
 

Lane Simonian
Posted: Thursday, December 11, 2014 2:32 PM
Joined: 12/12/2011
Posts: 5001


Here is the study which indicates why this is a good idea, but not a great idea. 


 

 2005 Nov 2;25(44):10180-7.

Deletion of the prostaglandin E2 EP2 receptor reduces oxidative damage and amyloid burden in a model of Alzheimer's disease.

Abstract

Epidemiological studies demonstrate that chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) in normal aging populations reduces the risk of developing Alzheimer's disease (AD). NSAIDs inhibit the enzymatic activity of cyclooxygenase-1 (COX-1) and inducible COX-2, which catalyze the first committed step in the synthesis of prostaglandins. These studies implicate COX-mediated inflammation as an early and potentially reversible preclinical event; however, the mechanism by which COX activity promotes development of AD has not been determined. Recent studies implicate the prostaglandin E2 (PGE2) E prostanoid subtype 2 (EP2) receptor in the development of the innate immune response in brain. Here, we report that deletion of the PGE2 EP2 receptor in the APPSwe-PS1DeltaE9 model of familial AD results in marked reductions in lipid peroxidation in aging mice. This reduction in oxidative stress is associated with significant decreases in levels of amyloid-beta (Abeta) 40 and 42 peptides and amyloid deposition. Aged APPSwe-PS1DeltaE9 mice lacking the EP2 receptor harbor lower levels of beta C-terminal fragments, the product of beta-site APP cleaving enzyme (BACE1) processing of amyloid precursor protein. Increases in BACE1 processing have been demonstrated in models of aging and AD and after oxidative stress. Our results indicate that PGE2 signaling via the EP2 receptor promotes age-dependent oxidative damage and increased Abeta peptide burden in this model of AD, possibly via effects on BACE1 activity. Our findings identify EP2 receptor signaling as a novel proinflammatory and proamyloidogenic pathway in this model of AD, and suggest a rationale for development of therapeutics targeting the EP2 receptor in neuroinflammatory diseases such as AD.


 

Even if you eliminate this receptor altogether or sharply inhibit the BACE1 enzyme you are still going to have oxidative stress.  My guess is that theste approaches would reduce the risk of Alzheimer's disease but not prevent it and would slow down the progression of Alzheimer's disease early on but not stop or reverse it.


 

If scientists were convinced of the following, Alzheimer's disease would be history of close to it.


 

Alzheimer's disease is caused by oxidative stress.  Oxidative stress leads to inflammation, amyloid, and aberrant tau proteins and each may further contribute to oxidative stress but they are not the principal causes of oxidative stress and thus are not the best targets to treat the disease.  

 

Good peroxynitrite scavengers will slow down the progression of Alzheimer's disease.  The best peroxynitrite scavengers will partially reverse Alzheimer's disease. 


Lane Simonian
Posted: Thursday, December 11, 2014 2:56 PM
Joined: 12/12/2011
Posts: 5001


Peroxynitrites activate microglia and activated microglia produce more peroxynitrites.  If you stop the activation of microglia is that enough to prevent Alzheimer's disease?  I don't have the answer to that question.  Here though is an example of what one should do to prevent and treat Alzheimer's disease because unlike all the other proposed interventions for Alzheimer's disease, peroxynitrite scavenging will work at any stage.


Peroxynitrite, the coupling product of nitric oxide and superoxide, activates prostaglandin biosynthesis

 2006 Sep;20(9):742-7.

Inhibition of nitric oxide synthase expression in activated microglia and peroxynitrite scavenging activity by Opuntia ficus indica var. saboten.

Abstract

Activated microglia by neuronal injury or inflammatory stimulation overproduce nitric oxide (NO) by inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS) such as superoxide anion, resulting in neurodegenerative diseases. The toxic peroxynitrite (ONOO-), the reaction product of NO and superoxide anion further contributes to oxidative neurotoxicity. A butanol fraction obtained from 50% ethanol extracts of Opuntia ficus indica var. saboten (Cactaceae) stem (SK OFB901) and its hydrolysis product (SK OFB901H) inhibited the production of NO in LPS-activated microglia in a dose dependent manner (IC50 15.9, 4.2 microg/mL, respectively). They also suppressed the expression of protein and mRNA of iNOS in LPS-activated microglial cells at higher than 30 microg/mL as observed by western blot analysis and RT-PCR experiment. They also inhibited the degradation of I-kappaB-alpha in activated microglia. Moreover, they showed strong activity of peroxynitrite scavenging in a cell free bioassay system. These results imply that Opuntia ficus indica may have neuroprotective activity through the inhibition of NO production by activated microglial cells and peroxynitrite scavenging activity.


Use of an opuntia ficus-indica extract and compounds isolated therefrom for protecting nerve cells
US 20050042311 A1

ABSTRACT
The present invention relates to a use of an ethyl acetate extract of Opuntia ficus-indica and compounds isolated therefrom for preventing and treating brain diseases such as Alzheimer's disease, stroke and Parkinson's disease, cell and tissue damage caused by ischemia, or cardiovascular system disease such as myocardial infarction.
The key to treating Alzheimer's disease is to find the optimum peroxynitrite scavengers.  This is not an especially daunting task.

Myriam
Posted: Thursday, December 11, 2014 4:06 PM
Joined: 12/6/2011
Posts: 3326


Thank you, Lane, for this information. Do you have any thoughts on Ashwaganda? I went to  Swanson's Vitamins website to reorder and found info on Ashwagandha. There's a plethora of choices. Here's an excerpt from a study: 

 

How Can Ashwagandha Fight Alzheimer’s?

Studies on Ashwagandha 

Researchers at Newcastle University have found that ashwagandha inhibits the formation of beta-amyloid plaques. These plaques, considered toxic to brain cells, accumulate in the brains of people with neurodegenerative diseases, such as Alzheimer’s. Because the studies were conducted in test tubes, however, researchers emphasize that more testing is needed.

At the National Brain Research Center (NBRC), scientists tested ashwagandha on mice with Alzheimer’s. After 20 days of treatment with ashwagandha, cognitive performance of the mice improved significantly. At the end of 30 days, their brain function had returned to normal and the amyloid plaques that had been present in the mice’s brains were reduced.

Moreover, the study showed that rather than altering brain chemistry directly, ashwagandha boosts a protein in the liver. This protein clears amyloid from the brain.

Side Effects of Ashwagandha 

Researchers caution that it’s too early for human trials of ashwagandha for Alzheimer’s. Although the dose given to mice was effective, it was very high. In high doses, the herb has shown to have a hypnotic effect, cause drowsiness and provoke intestinal problems. It’s also not recommended for people with hyperthyroidism or women who are pregnant.

Conclusions on Ashwagandha

Studies on ashwagandha show its promise as a treatment for memory loss and dementia in humans. But it’s still too early to tell whether it will someday become an alternative Alzheimer’s therapy.

Like any other remedy not prescribed by a doctor, people considering ashwagandha should consult with a physician to determine any potential drug interactions or side effects. Always talk to your doctor before you change your treatment regimen.


Lane Simonian
Posted: Thursday, December 11, 2014 7:14 PM
Joined: 12/12/2011
Posts: 5001


Sorry for not checking here first, Myriam.  I think a number of these herbs such as Aswagandha may be helpful. 
Lane Simonian
Posted: Saturday, December 13, 2014 10:36 AM
Joined: 12/12/2011
Posts: 5001


It was just pointed out to me by a fellow researcher that the EP2 receptor is a g protein-coupled receptors and overactivation of g protein-coupled receptors is one of the pathways that leads to the formation of peroxynitrites (ONOO-).  And peroxynitrites overactive this receptor to begin with by increasing production of prostaglandin (PGE2).   


 

The following article applies to dementia with lewy bodies but also applies to Alzheimer's disease. 


 


 

A Role for Activated Microglia and Peroxynitrite in Lewy Body Diseases – 

Implications for Prevention and Control 


 

Mark F. McCarty, Catalytic Longevity, markfmccarty@gmail.com 

Abstract 


 

Lewy body diseases – encompassing Parkinson’s disease, dementia with Lewy bodies, and Parkinson’s disease with late dementia – may reflect a vicious cycle of neuroinflammation in which aggregated alphasynuclein 

promotes microglial activation, and the peroxynitrite and cytokines produced by activated microglia in turn promote intraneuronal alpha-synuclein aggregation and neuronal death. If this model is correct, practical measures which dampen microglial activation and lessen peroxynitrite toxicity may aid the prevention and treatment of these disorders. Spirulina, a host of food polyphenols, DHA, astaxanthin, caffeine, a Mediterranean or plant-based diet, and exercise training have potential for blunting microglial activation. Measures which increase intraneuronal levels of urate and of glutathione – such as supplemental inosine, N-acetylcysteine, and phase 2 inducers – should mitigate the toxicity of peroxynitrite. Astaxanthin may suppress intraneuronal generation of superoxide and peroxynitrite by protecting the structure of mitochondrial inner membranes. Hence, it may eventually prove feasible to control or at least slow the progression of these devastating disorders with complex nutraceutical/lifestyle  strategies.  


 

And one more by the same author (I would take out the statins): 


 

Down-regulation of microglial activation 

may represent a practical strategy for 

combating neurodegenerative disorders 


 

Mark F. McCarty 

Natural Alternatives International, 1185 Linda Vista Dr., San Marcos, CA 92078, United States 

 

Received 1 September 2005; accepted 2 January 2006 


 

Summary Chronic neurodegenerative disorders are characterized by activation of microglia in the affected neural pathways. Peroxynitrite, prostanoids, and cytokines generated by these microglia can potentiate the excitotoxicity that contributes to neuronal death and dysfunction in these disorders – both by direct effects on neurons, and by impairing the capacity of astrocytes to sequester and metabolize glutamate. This suggests a vicious cycle in which the death of neurons leads to microglial activation, which in turn potentiates neuronal damage. If this model is correct,  measures which down-regulate microglial activation may have a favorable effect on the induction and progression of neurodegenerative disease, independent of the particular trigger or target involved in a given disorder. Consistent with this possibility, the antibiotic minocycline, which inhibits microglial activation, shows broad utility in rodent models of neurodegeneration. Other agents which may have potential in this regard include PPARc agonists, genistein, vitamin D, COX-2 inhibitors, statins (and possibly policosanol), caffeine, cannabinoids, and sesamin; some of these agents could also be expected to be directly protective to neurons threatened with excitotoxicity. To achieve optimal clinical outcomes, regimens which down-regulate microglial activation could be used in conjunction with complementary measures which address other aspects of excitotoxicity.  


 

And finally a helpful chart (for Parkinson's but again with implications for Alzheimer's disease). 


 


 


 

 


Lane Simonian
Posted: Saturday, December 13, 2014 10:56 AM
Joined: 12/12/2011
Posts: 5001


It is not a matter of whether Alzheimer's disease can be reversed, it is a matter of how far it can be reversed.  And what is the right combination of essential oils via aromatherapy, what is the optimal Mediterranean diet, what type of exercise and how often, and what types of herbs (lemon balm, turmeric, panax ginseng, cannabinoids, and possible several others)? 


There are several researchers working on this approach.  Hopefully, the naysaying by much of the Alzheimer's research community and charitable organizations will end and they will soon be able to embrace this approach.   


Lane Simonian
Posted: Saturday, December 13, 2014 1:36 PM
Joined: 12/12/2011
Posts: 5001


Peroxynitrites activate microglia which produce more peroxynitrites that activate NMDA receptors (leading to glutamate excitoxicity) which produce more peroxynitrites.  Scavenge the peroxynitrites and you stop the whole process (or at least slow it way down). 


 


 

 2001 Oct;79(2):445-55.

SIN-1-induced cytotoxicity in mixed cortical cell culture: peroxynitrite-dependent and -independent induction of excitotoxic cell death.

 

Minocycline Provides Neuroprotection Against N-Methyl-D-aspartate Neurotoxicity by Inhibiting Microglia1

Glutamate excitotoxicity to a large extent is mediated through activation of the N-methyl-D-aspartate (NMDA)-gated ion channels in several neurodegenerative diseases and ischemic stroke. Minocycline, a tetracycline derivative with antiinflammatory effects, inhibits IL-1β-converting enzyme and inducible nitric oxide synthase up-regulation in animal models of ischemic stroke and Huntington’s disease and is therapeutic in these disease animal models. Here we report that nanomolar concentrations of minocycline protect neurons in mixed spinal cord cultures against NMDA excitotoxicity. NMDA treatment alone induced microglial proliferation, which preceded neuronal death, and administration of extra microglial cells on top of these cultures enhanced the NMDA neurotoxicity. Minocycline inhibited all these responses to NMDA. Minocycline also prevented the NMDA-induced proliferation of microglial cells and the increased release of IL-1β and nitric oxide in pure microglia cultures. Finally, minocycline inhibited the NMDA-induced activation of p38 mitogen-activated protein kinase (MAPK) in microglial cells, and a specific p38 MAPK inhibitor, but not a p44/42 MAPK inhibitor, reduced the NMDA toxicity. Together, these results suggest that microglial activation contributes to NMDA excitotoxicity and that minocycline, a tetracycline derivative, represents a potential therapeutic agent for brain diseases.


 

 
 2011 Feb 18;286(7):4991-5002. doi: 10.1074/jbc.M110.169565. Epub 2010 Nov 16.

Neuroprotection by minocycline caused by direct and specific scavenging of peroxynitrite.

 
 
Minocycline is just one peroxynitrite scavenger.  Cannabinoids in marijuana, eugenol in various essential oils, and ferulic acid, syringic acid, p-coumaric acid, vanillic acid, and maltol in panax ginseng are others.  In a lab or clinical trials, just keeping hitting Alzheimer's disease with powerful peroxynitrite scavengers and see what happens. 

Serenoa
Posted: Wednesday, December 17, 2014 6:48 PM
Joined: 4/24/2012
Posts: 484


So what causes the whole COX-2, PGE2, PGR2, microglia inflamation? High glucose.

 Molecular mechanisms of high glucose-induced cyclooxygenase-2 expression in monocytes

 

Abstract

The cyclooxygenase (COX)-2 enzyme has been implicated in the pathogenesis of several inflammatory diseases. However, its role in diabetic vascular disease is unclear. In this study, we evaluated the hypothesis that diabetic conditions can induce COX-2 in monocytes. High glucose treatment of THP-1 monocytic cells led to a significant three- to fivefold induction of COX-2 mRNA and protein expression but not COX-1 mRNA. High glucose-induced COX-2 mRNA was blocked by inhibitors of nuclear factor-kappaB (NF-kappaB), protein kinase C, and p38 mitogen-activated protein kinase. In addition, an antioxidant and inhibitors of mitochondrial superoxide, NADPH oxidase, and glucose metabolism to glucosamine also blocked high glucose-induced COX-2 expression to varying degrees. High glucose significantly increased transcription from a human COX-2 promoter-luciferase construct (twofold, P < 0.001). Promoter deletion analyses and inhibition of transcription by NF-kappaB superrepressor and cAMP-responsive element binding (CREB) mutants confirmed the involvement of NF-kappaB and CREB transcription factors in high glucose-induced COX-2 regulation. In addition, isolated peripheral blood monocytes from type 1 and type 2 diabetic patients had high levels of COX-2 mRNA, whereas those from normal volunteers showed no expression. These results show that high glucose and diabetes can augment inflammatory responses by upregulating COX-2 via multiple signaling pathways, leading to monocyte activation relevant to the pathogenesis of diabetes complications.

 

 


Lane Simonian
Posted: Wednesday, December 17, 2014 8:37 PM
Joined: 12/12/2011
Posts: 5001


This connection between glucose and microglia activation is quite important. The pathway is via protein kinase C, p38 MAPK, and peroxynitrites. 


 

Prostaglandins generated by cyclooxygenase (COX) have been implicated in hyperglycemia-induced endothelial dysfunction. However, the role of individual COX isoenzymes as well as the molecular mechanisms linking oxidative stress and endothelial dysfunction in diabetes remains to be clarified. 


Human aortic endothelial cells were exposed to normal (5.5 mmol/L) and high (22.2 mmol/L) glucose. Glucose selectively increased mRNA and protein expression of COX-2. Its upregulation was associated with an increase of thromboxane A2 and a reduction of prostacyclin (PGI2) release. Glucose-induced activation of PKC resulted in the formation of peroxynitrite and tyrosine nitration of PGI2 synthase. 


 

http://www.pubfacts.com/detail/12600916/High-glucose-causes-upregulation-of-cyclooxygenase-2-and-alters-prostanoid-profile-in-human-endothel 


 

When high levels of glucose enter the brain as a result of being unable to get into other cells in the body (diabetes or pre-diabetes), it results in neuroinflammation due to the activation of microglia. 


Serenoa
Posted: Thursday, December 18, 2014 4:10 AM
Joined: 4/24/2012
Posts: 484


Thanks Lane. So high blood glucose basically does its damage through activating reactive oxygen species (ROS) which include peroxynitrite, right? As I remember from the other post, when insulin resistance prevents activation of the insulin receptor, glutathione is downregulated, and the beneficial PI3k pathway is inhibited. So high blood glucose leads to insulin resistance which keeps glucose from getting into the cell (or neuron in this case). Then this excess glucose causes inflammation by activating microglia through the prostaglandin receptor on the cell surface. Here's the quote from your above article,

 

 "Glucose-induced activation of PKC resulted in the formation of peroxynitrite and tyrosine nitration of PGI2 synthase."

 

 My question is if glucose can't get into a cell, how in the heck does it activate PKC or the COX-2 pathway in the microglial cell? Because we know that with insulin resistance glucose is prevented from entering the cell due to the GLUT4 receptor not being activated by the autophosphorylation of the insulin receptor substrate (how bout that for some fancy language!). My reason for the question is that I want to know the mechanisms by which hyperglycemia is doing damage and causing disease. We know it causes insulin resistance (that's one way), and we know neurons need insulin to function. We know that excess glucose in the blood is dangerous and leads to diabetic coma and other diabetic problems (but I don't know the mechanisms).  


Serenoa
Posted: Thursday, December 18, 2014 4:27 AM
Joined: 4/24/2012
Posts: 484


From my article above:

 

"These results show that high glucose and diabetes can augment inflammatory responses by upregulating COX-2 via multiple signaling pathways, leading to monocyte activation relevant to the pathogenesis of diabetes complications."

 

It seems that glucose has to enter some type of cell to activate PKC initiating this whole inflammatory process. However, insulin resistance would prevent that from happening (at least to some degree). This would show how insulin resistance, although harmful, is a protective measure taken by cells, because too much glucose in the cell is more dangerous than a lack of insulin stimulation.

 

Is it possible that this glucose-initiated damage happens before cells become insulin resistant? Or, is it possible that some cells don't become insulin resistant and keep taking in glucose which activates PKC and leads to production of prostoglandins which enter the blood and activate the inflammatory process in the microglia? 

 

 


Lane Simonian
Posted: Thursday, December 18, 2014 10:25 AM
Joined: 12/12/2011
Posts: 5001


You always asks such great questions, Serenoa.  It appears that high glucose levels initially activate protein kinase C which leads to the activation of the platelet derived growth factor receptors leading to more activation of protein kinase C.  Platelet derived growth factor receptors like the insulin receptor substrate may over time be inactivated by nitration, thus high glucose levels may be an initial rather than a latter problem.


 1996 Apr;45(4):507-12.

Enhanced expression of platelet-derived growth factor-beta receptor by high glucose. Involvement of platelet-derived growth factor in diabetic angiopathy.

Abstract

Coronary heart disease is a major complication of diabetic subjects, and platelet-derived growth factor (PDGF) has been implicated in the development of atherosclerosis. We investigated the effects of high glucose on expression of PDGF-beta receptor. In a binding assay with 125I-labeled PDGF-BB homodimer, high concentrations of glucose increased high-affinity binding of PDGF-BB on human monocyte-derived macrophages and rabbit aortic medial smooth muscle cells. Northern blot analysis confirmed the enhanced effect of glucose on expression of PDGF-beta receptor mRNA in human monocyte-derived macrophages. The protein kinase C inhibitor, staurosporin, completely suppressed an increase in PDGF-BB binding by high glucose, and high glucose significantly activated protein kinase C. These results indicated that PDGF-beta receptor expression was enhanced by high glucose through the activation of protein kinase C. Furthermore, we observed similar effects of high glucose on both PDGF-beta receptor expression and protein kinase C activation in rat mesangial cells and human capillary endothelial cells. Our results suggest that stimulation of the PDGF system is significantly involved in the development not only of diabetic atherosclerosis but also of microangiopathy.


To complicate matters further, the PGE2 receptor that leads to microglia activation is a g protein-coupled receptor and because of oxidation those receptors become inactivated over time as well.  So both high glucose levels and microglia activation may be early problems in Alzheimer's disease.  The main middle to late problem is the activation of NMDA receptors.


Lane Simonian
Posted: Thursday, December 18, 2014 10:59 AM
Joined: 12/12/2011
Posts: 5001


This helps nail down the pathway by which high levels of glucose activate microglia at least early on in Alzheimer's disease: 


 

High glucose concentrations increase endothelial cell permeability via activation of protein kinase C alpha.

http://www.ncbi.nlm.nih.gov/pubmed/9285638
 
 
 
We therefore concluded that PKC alpha and p38MAPK are interactively linked to the signaling cascade inducing TNFalpha in LPS-stimulated microglia, and that in this cascade, PKC alpha is requisite for the activation of p38MAPK, leading to the induction of TNF alpha. 

 
http://www.ncbi.nlm.nih.gov/pubmed/14602083 

 

 

Lane Simonian
Posted: Thursday, December 18, 2014 8:10 PM
Joined: 12/12/2011
Posts: 5001


Another chart and a few more steps in nailing down Alzheimer's disease (ebselen is a peroxynitrite scavenger; ONOO- is peroxynitrite).  Caspase-3 is the enzyme which activates the beta secretase and leads to the c-terminal fragment of the amyloid precursor protein in Alzheimer's disease. 


 

 


Lane Simonian
Posted: Thursday, December 18, 2014 8:49 PM
Joined: 12/12/2011
Posts: 5001


A couple of more good ones: 


 

Abstract

The amyloid-β precursor protein (APP) is directly and efficiently cleaved by caspases during apoptosis, resulting in elevated amyloid-β (Aβ) peptide formation. The predominant site of caspase-mediated proteolysis is within the cytoplasmic tail of APP, and cleavage at this site occurs in hippocampal neurons in vivo following acute excitotoxic or ischemic brain injury. Caspase-3 is the predominant caspase involved in APP cleavage, consistent with its marked elevation in dying neurons of Alzheimer’s disease brains and colocalization of its APP cleavage product with Aβ in senile plaques. Caspases thus appear to play a dual role in proteolytic processing of APP and the resulting propensity for Aβ peptide formation, as well as in the ultimate apoptotic death of neurons in Alzheimer’s disease.

 

http://www.sciencedirect.com/science/article/pii/S0092867400807485 


 

CONCLUSION: These results show that peroxynitrite induces apoptosis in photoreceptor cells and that such retinal damage appears to be mediated by caspase-3. The apoptotic process can be minimized by peroxynitrite scavenger urate, as well as by the caspase inhibitor Z-VAD-fmk. 


 

http://www.ncbi.nlm.nih.gov/pubmed/14704910 


 

My guess is that when you start to inhibit beta secretase activity it is already too late.  On the other hand, scavenging peroxynitrites and inhibiting caspase-3 activity is probably never too late and without some of the negative side effects of beta secretase inhibition. 

 

My question to researchers is how long would it take to assay plant compounds to find the most effective peroxynitrite scavengers to treat Alzheimer's disease. 


Lane Simonian
Posted: Friday, December 19, 2014 12:01 AM
Joined: 12/12/2011
Posts: 5001


Peroxynitrites initially activate microglia and activated microglia produce peroxynitrites which inhibit the function of microglia.



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 [amyloid] 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...However, just why the microglial cells, which cluster around the deposits, are inactivated or lose their functionality is still not fully understood.


And a possible explanation as to why microglia lose their functionality.


 1999 May;72(5):1948-58.

Metabolic impairment induces oxidative stress, compromises inflammatory responses, and inactivates a key mitochondrial enzyme in microglia.

Abstract

Microglial activation, oxidative stress, and dysfunctions in mitochondria, including the reduction of cytochrome oxidase activity, have been implicated in neurodegeneration. The current experiments tested the effects of reducing cytochrome oxidase activity on the ability of microglia to respond to inflammatory insults. Inhibition of cytochrome oxidase by azide reduced oxygen consumption and increased reactive oxygen species (ROS) production but did not affect cell viability. Azide also attenuated microglial activation, as measured by nitric oxide (NO.) production in response to lipopolysaccharide (LPS). It is surprising that the inhibition of cytochrome oxidase also diminished the activity of the alpha-ketoglutarate dehydrogenase complex (KGDHC), a Krebs cycle enzyme. This reduction was exaggerated when the azide-treated microglia were also treated with LPS. The combination of the azide-stimulated ROS and LPS-induced NO. would likely cause peroxynitrite formation in microglia. Thus, the possibility that KGDHC was inactivated by peroxynitrite was tested. Peroxynitrite inhibited the activity of isolated KGDHC, nitrated tyrosine residues of all three KGDHC subunits, and reduced immunoreactivity to antibodies against two KGDHC components. Thus, our data suggest that inhibition of the mitochondrial respiratory chain diminishes aerobic energy metabolism, interferes with microglial inflammatory responses, and compromises mitochondrial function, including KGDHC activity, which is vulnerable to NO. and peroxynitrite that result from microglial activation. Thus, activation of metabolically compromised microglia can further diminish their oxidative capacity, creating a deleterious spiral that may contribute to neurodegeneration.


Serenoa
Posted: Saturday, December 20, 2014 1:03 PM
Joined: 4/24/2012
Posts: 484


Lane, I just want to thank you again for all the research you have done and sharing it on this forum. It is good and relevant information and has been very helpful to my in-depth study of this disease.

 

All this has lead me to another quandary. Just when I thought I had a thorogh understanding of the causal mechanisms of this disease, another mystery pops up. I just learned that Down Syndrome and AD can have in common low blood pressure (hypotension), and AD has a well-documented association with hypotension as well as the more commonly known association with high blood pressure (hypotension). This seems to throw a wrench into my understanding of the causes of AD, and it strikes a chord with me because my mother has always had low blood pressure.

 

 So, the research goes on. I will post further if I can make some sense of this connection.


Lane Simonian
Posted: Sunday, December 21, 2014 10:05 AM
Joined: 12/12/2011
Posts: 5001


The relationship between hypotension and dementia has puzzled me as well. 


Perhaps low levels of homocysteine explain low blood pressure for people with Down syndrome.  Low blood pressure would result in less oxygen and glucose in the brain and this leads to more tyrosine phosphorylation and then to tyrosine nitration which would further reduce blood flow in the brain and negatively impair memory.


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


Your research might turn up further explanations.  I enjoy sharing research and learning from you and from all others here.


Serenoa
Posted: Sunday, December 21, 2014 1:17 PM
Joined: 4/24/2012
Posts: 484


Thanks for the clue and the article. It does seem that nitric oxide (NO) may be the critical factor in hypotension. On a quick search I found a connection to tumor necrosis factor (TNF). I like this connection because I think TNF can be linked to insulin resistance which has many connections to AD. Since NO has a role in peroxynitrite production, perhaps the overproduction of NO causing hypotension also leads to oxidative dammage. I'm just throwing stuff out there. It is perplexing.  

Inhibition of Ceramide Production Reverses TNF-Induced Insulin Resistance

Abstract

Ceramide has been implicated as a mediator of insulin resistance induced by tumor necrosis factor-α (TNF) in adipocytes. Adipocytes contain numerous caveolae, sphingolipid and cholesterol-enriched lipid microdomains, that are also enriched in insulin receptor (IR). Since caveolae may be important sites for crosstalk between tyrosine kinase and sphingolipid signaling pathways, we examined the role of increased caveolar pools of ceramide in regulating tyrosine phosphorylation of the IR and its main substrate, insulin receptor substrate-1 (IRS-1). Neither exogenous short-chain ceramide analogs nor pharmacologic increases in endogenous caveolar pools of ceramide inhibited insulin-induced tyrosine phosphorylation of the IR and IRS-1. However, inhibition of TNF-induced caveolar ceramide production reversed the decrease in IR tyrosine phosphorylation in response to TNF. These results suggest that TNF-independent increases in caveolar pools of ceramide are not sufficient to inhibit insulin signaling but that in conjunction with other TNF-dependent signals, caveolar pools of ceramide are a critical component for insulin resistance by TNF.


Lane Simonian
Posted: Sunday, December 21, 2014 8:42 PM
Joined: 12/12/2011
Posts: 5001


It is perplexing, but I think you are right: inducible nitric oxide and the subsequent production of peroxynitrites can lead to both insulin resistance and hypotension.  


Relatedely here is a study on inhibiting inducible nitric oxide synthase for diabetes which can be compared with the later study for Alzheimer's disease.


 2001 Oct;7(10):1138-43.

Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle.

Abstract

Inducible nitric oxide synthase (iNOS) is induced by inflammatory cytokines in skeletal muscle and fat. It has been proposed that chronic iNOS induction may cause muscle insulin resistance. Here we show that iNOS expression is increased in muscle and fat of genetic and dietary models of obesity. Moreover, mice in which the gene encoding iNOS was disrupted (Nos2-/- mice) are protected from high-fat-induced insulin resistance. Whereas both wild-type and Nos2-/- mice developed obesity on the high-fat diet, obese Nos2-/- mice exhibited improved glucose tolerance, normal insulin sensitivity in vivo and normal insulin-stimulated glucose uptake in muscles. iNOS induction in obese wild-type mice was associated with impairments in phosphatidylinositol 3-kinase and Akt activation by insulin in muscle. These defects were fully prevented in obese Nos2-/- mice. These findings provide genetic evidence that iNOS is involved in the development of muscle insulin resistance in diet-induced obesity.



 2005 Nov 7;202(9):1163-9. Epub 2005 Oct 31.

Protection from Alzheimer's-like disease in the mouse by genetic ablation of inducible nitric oxide synthase.

Abstract

Brains from subjects who have Alzheimer's disease (AD) express inducible nitric oxide synthase (iNOS). We tested the hypothesis that iNOS contributes to AD pathogenesis. Immunoreactive iNOS was detected in brains of mice with AD-like disease resulting from transgenic expression of mutant human beta-amyloid precursor protein (hAPP) and presenilin-1 (hPS1). We bred hAPP-, hPS1-double transgenic mice to be iNOS(+/+) or iNOS(-/-), and compared them with a congenic WT strain. Deficiency of iNOS substantially protected the AD-like mice from premature mortality, cerebral plaque formation, increased beta-amyloid levels, protein tyrosine nitration, astrocytosis, and microgliosis. Thus, iNOS seems to be a major instigator of beta-amyloid deposition and disease progression. Inhibition of iNOS may be a therapeutic option in AD.


Lane Simonian
Posted: Monday, December 22, 2014 6:30 PM
Joined: 12/12/2011
Posts: 5001


Noradrenaline may be the key independent variable in Alzheimer disease. High levels on noradrenaline in Alzheimer's disease correlate with hypertension and neuropsychiatric problems whereas low levels may be a factor in hypotension. The balance between the decreased release of noradrenaline and the increased release of noradrenaline differs between individuals. 


 

http://www.ncbi.nlm.nih.gov/pubmed/20626335 


 

http://www.ncbi.nlm.nih.gov/pubmed/8988954 


 


 


 


Lane Simonian
Posted: Monday, December 22, 2014 6:53 PM
Joined: 12/12/2011
Posts: 5001


Peroxynitrites can inhibit noradernaline release by damaging noradrenergic neurons or it can increase noradrenaline through NMDA receptor activation.


http://www.jneurosci.org/content/26/5/1343.full (the locus coeruleus is the site of noradrenaline synthesis).


http://www.ncbi.nlm.nih.gov/pubmed/2570360


http://www.ncbi.nlm.nih.gov/pubmed/24396435


The extent of NMDA receptor activation may make the difference between having high blood pressure and neuropsychiatric problems with Alzheimer's disease and not having them.



Serenoa
Posted: Tuesday, December 23, 2014 5:33 AM
Joined: 4/24/2012
Posts: 484


This is great information Lane. Let me take some time to explore this new connection. I'm feeling very good about the progress I have made in understanding this disease, and much of that progress is due to the research and comments you and others have shared on this message board.

 

Have a great Christmas!


Lane Simonian
Posted: Tuesday, December 23, 2014 9:59 AM
Joined: 12/12/2011
Posts: 5001


Very good, Serenoa.  Merry Christmas to you, too.  
Serenoa
Posted: Wednesday, December 24, 2014 11:09 AM
Joined: 4/24/2012
Posts: 484


Lane, this is very interesting. Glutathione peroxidase, an antioxidant that attacks hydrogen peroxide, may be responsible for creating insulin resistance and glucose intolerance. WHAT!??? How can this be? I've been reading about the connections of diabetes, artherosclerosis, etc to oxidative damage like peroxynitrites and I thought H2O2. Now this article is saying that ROS have a role in sensitizing insulin receptors (or something like that). How is hydrogen peroxide related to peroxynitrite, and can it be damaging to have too little hydorgen peroxide?

 

Development of insulin resistance and obesity in mice overexpressing cellular glutathione peroxidase

 

Abstract

Insulin resistance, a hallmark of type 2 diabetes, is associated with oxidative stress. However, the role of reactive oxygen species or specific antioxidant enzymes in its development has not been tested under physiological conditions. The objective of our study was to investigate the impact of overexpression of glutathione peroxidase 1 (GPX1), an intracellular selenoprotein that reduces hydrogen peroxide (H2O2) in vivo, on glucose metabolism and insulin function. The GPX1-overexpressing (OE) and WT male mice (n = 80) were fed a selenium-adequate diet (0.4 mg/kg) from 8 to 24 weeks of age. Compared with the WT, the OE mice developed (P < 0.05) hyperglycemia (117 vs. 149 mg/dl), hyperinsulinemia (419 vs. 1,350 pg/ml), and elevated plasma leptin (5 vs. 16 ng/ml) at 24 weeks of age. Meanwhile, these mice were heavier (37 vs. 27 g, P < 0.001) and fatter (37% vs. 17% fat, P < 0.01) than the WT mice. At 30–60 min after an insulin challenge, the OE mice had 25% less (P < 0.05) of a decrease in blood glucose than the WT mice. Their insulin resistance was associated with a 30–70% reduction (P < 0.05) in the insulin-stimulated phosphorylations of insulin receptor (β-subunit) in liver and Akt (Ser473 and Thr30 in liver and soleus muscle. Here we report the development of insulin resistance in mammals with elevated expression of an antioxidant enzyme and suggest that increased GPX1 activity may interfere with insulin function by overquenching intracellular reactive oxygen species required for insulin sensitizing.


Lane Simonian
Posted: Wednesday, December 24, 2014 4:39 PM
Joined: 12/12/2011
Posts: 5001


At first, I said to myself this study cannot be right, but here is an article explaining how low levels of hydrogen peroxide may actually reduce insulin resistance (by decreasing PTP1B--protein tryosine phosphatase 1B--low levels of hydrogen peroxide maintain levels of tyrosine phosphorylation needed to activate the phosphatidylinositol 3-kinase/Akt pathway).  Insulin works through insulin receptors and tyrosine phosphorylation of the insulin receptor substrate and the subsequent activation of Akt. 


 

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0027401 


 

http://www.ncbi.nlm.nih.gov/pubmed/11279262 


 

Below is a round about explanation of how high levels of hydrogen peroxide can contribute to insulin resistance (part of the answer is found in the second article). 


 

Superoxides combine with inducible nitric oxide to produce peroxynitrites throughout Alzheimer's disease and are converted by superoxide dismutase (an enzyme dependent on copper and zinc) during the early to mid-stages of the disease.  Amyloid oligomers attract copper and zinc increasing the production of hydrogen peroxide but this production stops after copper and zinc are entombed in amyloid plaques. 


 

http://www.ncbi.nlm.nih.gov/pubmed/16141213 


 

Hydrogen peroxide damage lipids in brain cells.  They can combine with nitrite anions (a product of peroxynitrite scavenging) to reform peroxynitrites. Nitrite anions can also be reduced by copper, zinc, and iron ions to directly nitrate proteins and receptors.  The nitration of the insulin receptor substrate is likely what causes insulin resistance in type 2 diabetes. 


 

http://www.ncbi.nlm.nih.gov/pubmed/21110800 


 

When peroxynitrites and hydrogen peroxide are scavenged they produce water, which is a de-nitrating agent.  Peroxynitrites via nitration however limit the production of reduced glutathione (via inhibition of the phosphatidylinositol/Akt pathway) which is a key peroxynitrite scavenger. Peroxynitrites also disable glutathione peroxidase which converts hydrogen peroxide into water.  High levels of peroxynitrites or the combination of hydrogen peroxide with peroxynitrites eventually disable the body's own antioxidant system. 


 

Several external antioxidants are both peroxynitrite and hydrogen peroxide scavengers.  According to one study, melatonin (which is also a peroxynitrite scavenger), scavenges hydrogen peroxide by 83%.  The big question is what percentage of peroxynitrites (and during the middle stages of the disease hydrogen peroxide) do you need to scavenge to not only stop the progression of Alzheimer's disease, but to partially reverse it. 


 

Thanks as always Serenoa, for helping me fit more pieces together. 


 


 


Lane Simonian
Posted: Wednesday, December 24, 2014 6:11 PM
Joined: 12/12/2011
Posts: 5001


A little bit of oxidation by peroxynitrites and hydrogen peroxide may increase tyrosine phosphorylation (or perhaps more accurately decrease tyrosine dephosphorylation) and cell survival.  Too much in the brain at least leads to tyrosine nitration, oxidation, and cell death.
 


 

Peroxynitrite signaling: receptor tyrosine kinases and activation of stress-responsive pathways and  1 2

Abstract 

Peroxynitrite, generated for example in inflammatory processes, is capable of nitrating and oxidizing biomolecules, implying a considerable impact on the integrity of cellular structures. Cells respond to stressful conditions by the activation of signaling pathways, including receptor tyrosine kinase-dependent pathways such as mitogen-activated protein kinases and the phosphoinositide-3-kinase/Akt pathway. Peroxynitrite affects signaling pathways by nitration as well as by oxidation: while nitration of tyrosine residues by peroxynitrite modulates signaling processes relying on tyrosine phosphorylation and dephosphorylation, oxidation of phosphotyrosine phosphatases may lead to an alteration in the tyrosine phosphorylation/dephosphorylation balance. The flavanol (−)-epicatechin is a potent inhibitor of tyrosine nitration and may be employed as a tool to distinguish signaling effects due to tyrosine nitration from those that are due to oxidation reactions.

 2006 Sep;13(9):1506-14. Epub 2006 Jan 20.

Two distinct signaling pathways regulate peroxynitrite-induced apoptosis in PC12 cells.

Abstract

The mechanisms of peroxynitrite-induced apoptosis are not fully understood. We report here that peroxynitrite-induced apoptosis of PC12 cells requires the simultaneous activation of p38 and JNK MAP kinase, which in turn activates the intrinsic apoptotic pathway, as evidenced by Bax translocation to the mitochondria, cytochrome c release to the cytoplasm and activation of caspases, leading to cell death. Peroxynitrite induces inactivation of the Akt pathway. Furthermore, overexpression of constitutively active Akt inhibits both peroxynitrite-induced Bax translocation and cell death. Peroxynitrite-induced death was prevented by overexpression of Bcl-2 and by cyclosporin A, implicating the involvement of the intrinsic apoptotic pathway. Selective inhibition of mixed lineage kinase (MLK), p38 or JNK does not attenuate the decrease in Akt phosphorylation showing that inactivation of the Akt pathway occurs independently of the MLK/MAPK pathway. Together, these results reveal that peroxynitrite-induced activation of the intrinsic apoptotic pathway involves interactions with the MLK/MAPK and Akt signaling pathways.


 

 2003 Apr 11;140-141:125-32.

Defenses against peroxynitrite: selenocompounds and flavonoids.

Abstract

The inflammatory mediator peroxynitrite, when generated in excess, may damage cells by oxidizing and nitrating cellular components. Defense against this reactive species may be at the level of prevention of the formation of peroxynitrite, at the level of interception, or at the level of repair of damage caused by peroxynitrite. Several selenocompounds serve this purpose and include selenoproteins such as glutathione peroxidase (GPx), selenoprotein P and thioredoxin reductase, or low-molecular-weight substances such as ebselen. Further, flavonoids, such as (-)-epicatechin, which occurs in green tea or cocoa as monomer or in the form of oligomers, can contribute to cellular defense against peroxynitrite.


 


 


Serenoa
Posted: Sunday, December 28, 2014 6:15 AM
Joined: 4/24/2012
Posts: 484


Excellent info. Thanks Lane.

 

Isn't it funny how understanding can evolve. More and more I'm realizing the importance of balance in biology. It seems most things are neither all good or all bad, but the imbalances between them are where disease takes hold.


Lane Simonian
Posted: Sunday, December 28, 2014 10:28 AM
Joined: 12/12/2011
Posts: 5001


Such a good observation, Serenoa. Sometimes the balance is disrupted by a genetic factor, but often times it is an external factor: whether it be an unhealthy diet, pollution, medications, a bacteria or virus, or stress (among others). 


 

I am travelling to see relatives, so I will be gone the next few days, but look forward to catching up when I return at the end of the week.   


Myriam
Posted: Monday, December 29, 2014 7:59 PM
Joined: 12/6/2011
Posts: 3326


Safe travels, Lane.
Lane Simonian
Posted: Monday, January 5, 2015 11:04 PM
Joined: 12/12/2011
Posts: 5001


Thanks, Myriam.  I had to delay my trip by a couple of days because of snow and thus missed seeing one of my nieces, but otherwise it was a nice visit.


In the open spaces between Reno and Boise I had plenty of time to think about Alzheimer's disease (and other matters), but no epiphanies.  I do believe that the right combination of antioxidants will before long change the course of the disease (and to a certain extent already has).




Myriam
Posted: Tuesday, January 6, 2015 12:29 AM
Joined: 12/6/2011
Posts: 3326


Great to see you here again, Lane. After 5 years since diagnosis, I still remain in the early stage, though in the last couple of months, I dropped from very early to early, meaning I have to write everything down. I think my move to a new place in north Seattle, the Holidays, meeting lots of new people, and getting a second puppy may have contributed to the decline. Feeling blessed, though! Didn't think I would be doing so well for so long. Thanks to Best Practices and your Great Research!
Lane Simonian
Posted: Tuesday, January 6, 2015 9:52 AM
Joined: 12/12/2011
Posts: 5001


You have done everything right, Myriam.  I am so impressed and inspired by you and so many others here.


When a lot of things are happening at once, it probably can lead to a slight decline.  I hope that you are enjoying your new place and your new puppy.


Research is one of my favorite activities.  I just wish that I could find more answers more quickly, but coming to this forum helps keep me thinking.


garyD.
Posted: Sunday, January 18, 2015 11:03 PM
Joined: 1/4/2015
Posts: 4


Clinical trials of a vaccine " Betabloc" ,made by Dublin-based Elan Pharmaceuticals, are under way in the UK. The vaccine attacks the protein beta-amyloid which builds up in Alzheimer's patients. Supposedly, the drug not only removes the proteins but can restore mental functions. They say this will be available in five years. Doesn't sound like it would work on my wife, Kay (62) who is in end stage. Maybe the next generation won't have to deal with this horrible disease. To further check this info. out: do a search on James Chapman, Daily Mail
Harry Cayton
Betabloc
Elan (Perrigo bought them) pharmaceuticals
Dr. Peter St George-Hyslop of the University of Toronto
I don't have time to fully check this out, but please pursue and post back what you find. My wife is dying and she would never get in a clinical trial, but maybe your loved one can.......gary