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A Genetic Answer to the Alzheimer's Riddle?
Myriam
Posted: Wednesday, August 14, 2013 11:49 PM
Joined: 12/6/2011
Posts: 3326


What if we could pinpoint a hereditary cause for Alzheimer's, and intervene to reduce the risk of the disease? We may be closer to that goal, thanks to a team at the University of Kentucky. Researchers affiliated with the UK Sanders-Brown Center on Aging have completed new work in Alzheimer's genetics; the research is detailed in a paper published today in the Journal of Neuroscience. 

 

Emerging evidence indicates that, much like in the case of high cholesterol, some Alzheimer's disease risk is inherited while the remainder is environmental. Family and twin studies suggest that about 70 percent of total Alzheimer's risk is hereditary. 

 

Recently published studies identified several variations in DNA sequence that each modify Alzheimer's risk. In their work, the UK researchers investigated how one of these sequence variations may act. They found that a "protective" genetic variation near a gene called CD33 correlated strongly with how the CD33 mRNA was assembled in the human brain. The authors found that a form of CD33 that lacked a critical functional domain correlates with reduced risk of Alzheimers disease. CD33 is thought to inhibit clearance of amyloid beta, a hallmark of Alzheimers disease. 

 

The results obtained by the UK scientists indicate that inhibiting CD33 may reduce Alzheimer's risk. A drug tested for acute myeloid leukemia targets CD33, suggesting the potential for treatments based on CD33 to mitigate the risk for Alzheimer's disease. Additional studies must be conducted before this treatment approach could be tested in humans. 

 

Authors on the paper, titled "CD33 Alzheimer's Risk-Altering Polymorphism, CD33 Expression, and Exon 2 Splicing" are Manasi Malik (lead author), Steven Estus, James F. Simpson, and Ishiti Parikh, all of the UK Department of Physiology; Bernard R. Wilfred and Peter Nelson of the UK Department of Pathology, and David W. Fardo of the UK Department of Biostatistics. 


Vita99
Posted: Friday, August 23, 2013 6:52 AM
Joined: 9/4/2012
Posts: 469


I often puzzle over the genetics connection.  My mother's parents lived to a vigorous age 90 without cognitive problems.  My mom is only 76 and it looks to me that she is moving into a new phase these last few weeks.  



Mimi S.
Posted: Friday, August 23, 2013 9:02 AM
Joined: 11/29/2011
Posts: 7027


I guess the answer is: sometimes it is and sometimes we know of no one in the family who suffered from dementia. Any one on our extended family or back in the generations. Of course, it was often undiagnosed in earlier times.
Lane Simonian
Posted: Friday, August 23, 2013 9:40 AM
Joined: 12/12/2011
Posts: 5001


CD33 seems to play an anti-inflammatory role via the activation of the phosphatidyinositol 3-kinase (which is low in Alzheimer's disease) and an inflammatory role via the activation of p38 MAPK (which is high in Alzheimer's disease).   

 

http://www.ncbi.nlm.nih.gov/pubmed/15597323 

 

Nordihydroguaiaetic acid (that's a mouthful) is a lignan (a polyphenol) and a peroxynitrite scavenger that downregulates CD33.  Here are some of its effects. 

 

Nordihydroguaiaretic acid (NDGA) is a natural lignan that is primarily isolated and commercially produced from the desert creosote bush, Larrea tridentata, which has long been used in traditional medicine for the treatment of several illnesses including diabetes and inflammation []. It is estimated that NDGA comprises approximately 5% to 10% of the dry weight of the leaves, and this corresponds to 80% of all the phenolic compounds in the resin []. Cell culture and animal model studies have demonstrated that NDGA has biological properties, including anticarcinogenic, antidiabetic, antiviral, antioxidant, and anti-inflammatory activities [].

 

 

It is well established that NDGA has biological properties, such as anticarcinogenic [], antidiabetic, antiviral, antioxidant, and anti-inflammatory activities in human cell cultures and animal models [, ]. Furthermore, NDGA has beneficial health properties, including the growth inhibition of human cancers in vivo [, ], the degradation of preformed Alzheimer's beta-amyloid fibrils in vitro [], and the protection of cultured rat hippocampal neurons against the toxicity of the amyloid beta-peptide [].

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3596923/ 

 

I have always liked plants, but these days I am loving them. 

 

 


Lane Simonian
Posted: Friday, August 23, 2013 10:45 AM
Joined: 12/12/2011
Posts: 5001


Happy! Happy! Happy!  This story make me happy. 

 

Everyday foods may prevent Alzheimer’s and Parkinson’s disease, say UTEP researchers

 

Creosote bush (Creosote Larrea Tridentata) found in El Paso contain polyphenols that help intervene in the process of protein misfolding.  

Creosote bush (Creosote Larrea Tridentata) found in El Paso contain polyphenols that help intervene in the process of protein misfolding.

 

EL PASO – Imagine a place where drinking a glass of milk and munching on cheese and crackers is all you need to prevent Alzheimer’s and Parkinson’s disease.

According to Dr. Mahesh Narayan’s, associate professor of chemistry at The University of Texas at El Paso, this fairy tale scenario could soon be a reality.

 

 

In recent studies, Narayan has shown that everyday spices such as turmeric, most commonly found in Indian food, neem, almond oil and the creosote bush hold the potential for unlocking the key ingredients in the prevention of neurodegenerative diseases.

 

NEUROLOGICAL DISORDERS

A range of experimental approaches have revealed a tight connection between neurodegenerative diseases and oxidative stress. Free radicals are implicated in a variety of acute and chronic neurodegenerative disorders, such as cerebral ischemia and Alzheimer’s disease; ROS are thought to be responsible for neuronal injury []. A study using hippocampal neurons from rats demonstrated that NDGA [nordihydroguaiaretic acid in creosote bushes] prevents neuronal injury and accumulation of ROS. Also, the cultured neurons were protected against the toxicity of amyloid β-peptide (Aβ); Aβ-induced accumulation of ROS and intracellular calcium were suppressed []. The study concluded that NDGA has a neuroprotective role which is likely mediated by its lipoxygenase inhibitor/antioxidant properties. As such, it could potentially play a key role in the disruption of neurodegenerative pathways that contribute to the pathophysiology of Alzheimer’s disease and other neurological disorders [, ]. Indeed, as mentioned, NDGA is a very potent inhibitor of 5-lipoxygenase in different tissues. It also has considerable inhibitory activity against cyclooxygenase, resulting in a inhibitory effect in arachidonic acid metabolism, and limited n-metyl-D-aspartate (NMDA, a subclass of glutamate receptor) induced neuronal toxicity [].

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2927326/ 

 

Finding effective non-toxic doses is the key. 

 

A Mexican environmental historian finally comes home (me). 

 

 

 

 


Myriam
Posted: Friday, August 23, 2013 11:25 AM
Joined: 12/6/2011
Posts: 3326


    Clapping Smiley

So happy you're here...errr...home.

 


Vita99
Posted: Saturday, August 24, 2013 7:20 AM
Joined: 9/4/2012
Posts: 469


Lane, I wrote a response to a post  yesterday in another thread regarding Carlos Oliveira and it is missing in action  I looked at the article on copper in the alz reading room and his posts. He is adamant that a physician be involved in the prescription of the supplements he is using for his aunt.  Have you been in contact with him?  He indicates that dementia (in his experience) can be stopped in its tracks by the right combination of supplements.   


 

I also read one of your old post regarding coconut oil, I think from 2011.  Conventional wisdom is that the benefits come from the ketones, benefiting a brain that is insulin resistant and unable to use glucose as a fuel efficiently.  Do you believe that coconut oil perhaps works more like an antioxidant?    

Oh yes, I want the creosote bush too.  


Lane Simonian
Posted: Saturday, August 24, 2013 11:02 AM
Joined: 12/12/2011
Posts: 5001


For awhile Carlos and I were in contact once or twice a week.  I have not heard from him recently, but always try to follow his posts on the Alzheimer's Reading Room--really smart and nice guy.   

 

The results he has seen in his aunt and in others with dementia seem to provide strong empirical evidence that the supplements are working.  Together, we have been piecing together their role as antioxidants and how they may also lead to significant improvements in behavior. 

 

Carlos is more cautious and wise in recommending always check with a doctor before taking supplements than I am.  For the essential oils, I know now most but probably not all of the potentially adverse reactions (for example, the possible drug interactions with essential oils are not well known).  Carnosine and l-acetyl-carnitine may be relatively safe; less is known about glucuronolactones.  I might say always check with a doctor, an herbalist, and an aromatherapist because each will likely know something that the other does not (how many doctors for example know as much about aromatherapy as an aromatherapist and how many aromatherapists would know about possible drug interactions).  

  

Great question about ketones--yes they provide an alternative energy source to the brain and they are antoxidants.   

  

http://pubs.acs.org/doi/abs/10.1021/ja984358v?journalCode=jacsat 

 

One note of caution about the creosote bush, it should be consumed only in low doses by people without liver problems. 

 

 

Although controversial, Creosote bush, Larrea tridentata (Sesse and Moc. ex DC) Coville, is used to treat a variety of illnesses including

infertility, rheumatism, arthritis, diabetes, gallbladder and kidney stones, pain and inflammation. Recently, it has been used as a nutritional

supplement. The primary product extracted from this common plant of the arid regions of northern M´exico and Southwestern United States

is the potent antioxidant nordihydroguaiaretic acid (NDGA). It was widely used during the 1950s as a food preservative and to preserve

naturals fibers. Later it was banned after reports of toxicity during the early 1960s. Renal and hepatotoxicity are also reported for chronic use

of creosote bush and NDGA. This article reviews traditional and contemporary uses and pharmacology, including toxicology of this plant

widely used in Mexican traditional medicine.

 

http://etnof.fciencias.unam.mx/P3Pub/Pdf/009.pdf 

 

CONCLUSIONS:

Relatively small intakes of Larrea tincture, or topical application of extracts in Ricinus oil, are safe when prescribed by a clinically trained botanical prescriber. Larrea should be used with caution in persons with a history of previous, or current, liver disease. It may be preferable to avoid the use of Larrea capsules because they have been associated with potentially dangerous overdosing.

 

http://www.ncbi.nlm.nih.gov/pubmed/11327523 

 

 

 

 

 

 

 

With proper caution and assistance, most or all of these antioxidant containing natural products should help considerably in the treatment of Alzheimer's disease.  And it could be the case the more of them (not heavier doses) the better.  

 

 

 


Vita99
Posted: Sunday, August 25, 2013 7:15 AM
Joined: 9/4/2012
Posts: 469


Thanks, Lane.  Perhaps doctors in Brazil are more willing to delve into supplements to treat diseases.  I know that European doctors do.


Coconut oil may provide a double whammy for AD and other neurological diseases.  There ares probably multiple pathways to this disease and ketones appear to help with several neurological illnesses including seizures.  I will start the coconut oil experiment with Mom as soon as the pills get here and will report any progress or lack of. 


Lane Simonian
Posted: Sunday, August 25, 2013 8:50 PM
Joined: 12/12/2011
Posts: 5001


Yes, the aversion to supplements seems to be much higher among medical professionals in the United States than elsewhere than in the world.  The same also goes for research into natural products to treat Alzheimer's disease--almost all of its occurs outside of the United States. 

 

Here is some more on coconut oil from the Alzheimer's Reading Room (both positive and negative). 

http://www.alzheimersreadingroom.com/2012/07/Alzheimers-Coconut-Oil-Antioxidants.html 

 

 Coconut oil does not seem to help those who have certain genetic risk factors for Alzheimer's disease (particularly those with the APOE4 gene who have problems processing saturated fats).  And it probably should not be combined with many other saturated fats.  The phenolic compound in the oil partially offset the potential problems posed by the saturated fats.  Dr. Tanzi does not note that ketones, too, are antioxidants.  Finally ferulic acid is an antioxidant that not only helps somewhat with memory it helps considerably with behavior. 


Vita99
Posted: Monday, August 26, 2013 6:47 AM
Joined: 9/4/2012
Posts: 469


Thanks again, Lane.  Carlos has quite a few posts following this article and there is a post by Mary Newport. What I found most interesting was that Carlos' aunt did not tolerate the coconut oil in her diet but when they massaged her arms with it she did show improvement.
Lane Simonian
Posted: Monday, August 26, 2013 2:51 PM
Joined: 12/12/2011
Posts: 5001


I forgot to read the comments following the article, a number of ones which were quite good including those by Carlos and Mary Newport.  Coconut oil in the diet can cause stomach upset in some cases.  It would seem like an essential oil using coconut oil as a carrier oil would be a good combination.  I look forward to hearing how the coconut oil pills works for your mother.
Myriam
Posted: Monday, August 26, 2013 3:05 PM
Joined: 12/6/2011
Posts: 3326


 I just ordered coconut oil in capsule form. It calls for 3 capsules a day. The order will arrive within a week and will let you know of it's effect on me. Call me guinea pig...anything for the cause.


Serenoa
Posted: Monday, August 26, 2013 3:19 PM
Joined: 4/24/2012
Posts: 484


Coconut oil is great. I use it to cook with and put on my skin. I had my mom using it but it was difficult to get her to do it consistently. The pills are a good way to do it, but they are large and difficult to swallow. I didn't notice any dramatic difference but she has APOE4, and I don't think she used enough or consistently.

 

Coconut oil fits with the idea that fat in the diet is good. Never eat anything that's "Low Fat." It's just sugar and carbs, and they are bad for AD, cardiovascular, cholesterol, body fat and everything else.


Vita99
Posted: Tuesday, August 27, 2013 6:24 AM
Joined: 9/4/2012
Posts: 469


I agree that the fat is not the problem in many diets.  It is the combination of fat and carbohydrate.  I have had to be my own guinea pig and a reduction  in carbs has worked wonders for me.  I am a former dietitian and if I had been following what I learned about the diabetic diet I would have gone from being pre diabetic to diabetic by now.
Vita99
Posted: Tuesday, August 27, 2013 6:50 AM
Joined: 9/4/2012
Posts: 469


Myriam, you mentioned using aromatherapy.  I am not doing it too well.  I seem to be using too much oil and it is evaporating as I leave the containers open for the scent to drift through the room.  Do you use a diffuser?  I wonder if just keeping the oil in a covered dish when not  used would be OK?
Myriam
Posted: Wednesday, August 28, 2013 2:07 AM
Joined: 12/6/2011
Posts: 3326


I keep each of the bottles tightly shut and only open them to sniff the scent right out of the bottle twice a day.  I've been doing it for a couple of years and I give credit to it for keeping me in the MCI stage.
Serenoa
Posted: Wednesday, August 28, 2013 9:48 AM
Joined: 4/24/2012
Posts: 484


Vita99, so true about the carbs. It's interesting that you were a Dietitian. It seems to me that starting back in the early 1900's, but exponentially increasing since the 50's, there has been easy access to highly processed, high-sugar snacks and candy that is unpressidented in human history. Candy bars at every checkout, milkshakes and icecream at every corner, even a "normal" dinner includes Craft Macaroni and Cheese which is high in processed carbs and has no nutritional value.

 

 

There is no way that this shift in diet is not having a huge negative effect on our health!


Lane Simonian
Posted: Wednesday, August 28, 2013 7:25 PM
Joined: 12/12/2011
Posts: 5001


The Surprising Ways Grains Are Destroying Your Brain

 

Eyecatching headline, but the neurologist agrees with Vita and Serenoa.   

 

A diet high in carbohydrates, sugar, salt, and certain types of fats (such as Omege 6-fatty acids and animal saturated fats) increase the risk for Alzheimer's disease whereas various spices, Omega 3-fatty acid, and polyphenols from various fruits, vegetables, and oils reduce the risk for Alzheimer's disease 

 

Because of the inflammation they cause me I can no longer eat most grains.  In the short-run and in the long-run, many of us probably do better without them. 

 

I got side-tracked, here is the article itself (it's not just diet in some case, but in other cases a healthy diet may at least delay the onset of Alzheimer's disease). 

  

Medical science is making meaningful strides in terms of reducing heart disease and some forms of cancer. But why are we desperately losing the battle when it comes to Alzheimer’s disease? 

 
The statistics take your breath away. We’ve already got 5.4 million Alzheimer’s patients right here in the U.S., and that number is poised to double by 2030. And the cost for caring for these folks is estimated to be around $200 billion each year, almost triple what's spent in treating cancer patients.
 
Recently, news reports again revealed another multi-million dollar failure in an attempt to develop a meaningful treatment for this disease. So as of now, there remains no “magic pill” for this malady.

 

But the most heart-wrenching factor in this discussion is the simple, well-supported fact that Alzheimer’s disease is preventable. The disease that not only robs individuals of their ability to care for themselves, but emotionally cripples their families as well, is a situation that doesn’t need to happen.

 

Lifestyle factors are profoundly influential in determining risk for Alzheimer’s, and yet, perhaps because they cannot be monetized, no one is bringing this information to public awareness. 

 

For example, researchers at the prestigious Mayo Clinic recently published a report showing that a lower carb, higher fat diet is associated with a 42% risk reduction for dementia, the most common form being Alzheimer’s.
 
More recently, the New England Journal of Medicine showed us that even small elevations of blood sugar translate into increased risk for becoming demented. And blood sugar relates to dietary choices. Higher carbs means higher risk for dementia.
 
Alzheimer’s can, and more importantly should be prevented, even if it means, and perhaps especially if it means that preventing this disease will translate to a reduction in sales of pharmaceuticals.
 
So what can you do, today, to meaningfully reduce your risk for Alzheimer's disease, a disease for which the current medical armamentarium offers no treatment solution? 
 

 
1. Adopt a dramatically lower carbohydrate diet. That means counting carbs and keeping them below 60-80 grams daily.
 
2. Add more fat. Fat is a super fuel for the brain, protecting and nourishing delicate brain cells. Good choices include extra-vrgin olive oil, coconut oil, grass-fed beef, and wild caught fish.
 
3. Begin an aerobic exercise program targeting at least 20 minutes of sustained aerobics daily.
 
4. Take a DHA supplement. DHA, a specific omega-3, targets the genes that actually allow you to grow new brain cells specifically in the brain's memory center.

 

 

 

David Perlmutter, MD , FACN is a Board-Certified neurologist and Fellow of the American College of Nutrition. He is the author of Grain Brain, The Surpirising Truth About Wheat, Carbs and Sugar – Your Brain’s Silent Killers
 

 

Vita99
Posted: Thursday, August 29, 2013 6:51 AM
Joined: 9/4/2012
Posts: 469


Yes, the grain that was the staff of life for our ancestors has been modified & hybridized.  The article states that 60 to 80 grams of carbohydrates are a goal.  Yikes, that is hard.  One hundred to 150 is more realistic, especially if you are not a meat eater and like vegetables.  

 


Lane Simonian
Posted: Thursday, August 29, 2013 11:07 AM
Joined: 12/12/2011
Posts: 5001


Although not specific to Alzheimer's disease, I found this comment on Dr. Perlmutter's article quite interesting and right to Vita's point.

 

Dawn Krahn

 

We do not have the same grain that has been consumed for 1000's of years. In the 60's grain was 5% gluten, now it is 50% gluten, now we have an epidemic of celiac disease and glucose intolerance. The grain was changed to make for fast bread production commercially, what used to take 12 - 24 hours to rise, now takes 2 hours to rise because of the extra gluten. Gluten is very hard on the digestive tract and body. Do some research on gluten, celiac disease, and gluten intolerance to start and go from there, it is very interesting. The University where I live is working on a wheat variety that is very low in gluten, like we used to have, to address the huge epidemic of gluten intolerance.

 


Lane Simonian
Posted: Thursday, August 29, 2013 11:50 AM
Joined: 12/12/2011
Posts: 5001


Now this one is a more specific to Alzheimer's disease. 

 

Conclusions  A possible association exists between progressive cognitive impairment and celiac disease...Three patients improved or stabilized cognitively with gluten withdrawal. 

 

 http://archneur.jamanetwork.com/article.aspx?articleid=792544 

 

And look at the culprit in both cases: peroxynitrites (specifically peroxynitrite-mediated nitration of tyrosine). 

 

Nitrotyrosine in plasma of celiac disease patients as detected by a new sandwich ELISA

 

Both nitrotyrosine and NOX [nitric oxide] levels declined when the patients were on a gluten-free diet, suggesting a relation between intestinal inflammation and plasma nitrotyrosine and NOX levels.

 

http://www.sciencedirect.com/science/article/pii/S0891584998001841 

 

Roles of 3-nitrotyrosine- and 4-hydroxynonenal-modified brain

proteins in the progression and pathogenesis of Alzheimer ’s disease

 

https://www.as.uky.edu/sites/default/files/butterfield/Butterfield%20et%20al%202011%20Free%20Radic%20Res%2045%2059-72.pdf 

 

 

 

 

 


Lane Simonian
Posted: Thursday, August 29, 2013 5:05 PM
Joined: 12/12/2011
Posts: 5001


I never thought Celiac's disease would help me understand Alzheimer's disease and that Alzheimer's disease would help me understand Celiac's disease but here is an interesting connection.

 

tTG (tissue transglutaminase) is best known for its link with celiac disease.

 

tTG is believed to be involved in several neurodegenerative disorders including Alzheimer, Parkinson and Huntington diseases.

 

http://en.wikipedia.org/wiki/Tissue_transglutaminase 

 

Tissue transglutaminase initially activates (and later deactivates) phospholipase C which is the trigger for Alzheimer's disease.

 

http://www.ncbi.nlm.nih.gov/pubmed/10527931 

 

The activation of phospholipase C leads to the production of peroxynitrites which damage tissues in the intestines (Celiac's disease) and suppresses neurotransmitter levels and causes the death of brain cells (Alzheimer's disease). 

 

Great (which I say half-sarcastically), we can now probably add Celiac's disease to the list of risk factors for Alzheimer's disease.

 

http://www.sciencedaily.com/releases/2006/10/061010022602.htm 


Serenoa
Posted: Thursday, August 29, 2013 9:43 PM
Joined: 4/24/2012
Posts: 484


This tTG molecule deserves more investigation, and the possible connection to Celiac Disease and dietary gluten is very interesting. Lane's above article stated something that seems familiar, and maybe linked to the blood-brain barrier/vascular damage I've been studying lately:

 

 

"In the extracellular space, tTG binds to proteins of the extracellular matrix (ECM),[5] binding particularly tightly to fibronectin.[6] Extracellular tTG has been linked to cell adhesion, ECM stabilization, wound healing, receptor signaling, cellular proliferation, and cellular motility."

 

 

Things like "cell adhesion" within or around the capillaries that form the blood-brain barrier could result in blockages, or, receptor signaling disruption might stop amyloid from being moved out of the brain. I don't know, it just seems familiar. Have to do more reading.

  

 

 When I was searching for an alternative doctor for mom, I called Dr. Pearmutter's office, as he has a good reputation. He wanted $800 for a consultation (and didn't take insurance). We did not see him.


Lane Simonian
Posted: Thursday, August 29, 2013 11:39 PM
Joined: 12/12/2011
Posts: 5001


Just when I thought I was headed down a blind alley, I was rescued by this study. 

 

 

2012 May;227(5):2089-96. doi: 10.1002/jcp.22938.

Tissue transglutaminase promotes PDGF/PDGFR-mediated signaling and responses in vascular smooth muscle cells.

Source

Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

Abstract

Although the pivotal role of platelet derived growth factor (PDGF)-mediated signaling in vascular diseases was demonstrated, the pathophysiological mechanisms driving its over-activation remain incompletely understood. Tissue transglutaminase (tTG) is a multifunctional protein expressed in the vasculature, including smooth muscle cells (SMCs), and implicated in several vascular pathologies. The goal of this study is to define the regulation of PDGF-BB/PDGFRβ-induced signaling pathways and cell responses by tTG in vascular SMCs. We find that in human aortic SMCs, shRNA-mediated depletion and over-expression of tTG reveals its ability to down-regulate PDGFRβ levels and induce receptor clustering. In these cells, tTG specifically amplifies the activation of PDGFRβ and its multiple downstream signaling targets in response to PDGF-BB. Furthermore, tTG promotes dedifferentiation and increases survival, proliferation, and migration of human aortic SMCs mediated by this growth factor. Finally, PDGF-BB stimulates tTG expression in human aortic SMCs in culture and in the blood vessels in response to injury. Together, our results show that tTG in vascular SMCs acts as a principal enhancer within the PDGF-BB/PDGFRβ signaling axis involved in phenotypic modulation of these cells, thereby suggesting a novel role for this protein in the progression of vascular diseases.

 http://www.ncbi.nlm.nih.gov/pubmed/21769866 

 

Among other things, this is a pathway that leads to platelet aggregation (and thus vascular disease), the formation of amyloid plaques, and peroxynitrites. 

  

http://www.ncbi.nlm.nih.gov/pubmed/12645527 

 

A day of surprising finds. 


Lane Simonian
Posted: Thursday, August 29, 2013 11:54 PM
Joined: 12/12/2011
Posts: 5001


Glucose is another factor which activates platelet derived growth factor receptors and increases the risk for vascular diseases and Alzheimer's disease. 

 

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.

Source

Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.

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.

 

 

 


Vita99
Posted: Friday, August 30, 2013 7:22 AM
Joined: 9/4/2012
Posts: 469


Great new stuff Lane!  I ordered one of Dr Perlmutter's books from the library, The Better Brain Book.  Wow, $800?  Will not take insurance?  I guess he practices in an area where his services  are affordable!
Lane Simonian
Posted: Friday, August 30, 2013 10:13 AM
Joined: 12/12/2011
Posts: 5001


This may have been the article you were thinking of Serenoa. 

 

Tissue Transglutaminase: A Novel Therapeutic Target in Cerebral Amyloid Angiopathy

Wilhelmus M.M.M. · de Jager M. · Drukarch B.
 

 

Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
Neurodegenerative Dis 2012;10:317–319 (DOI:10.1159/000333224)
 

Abstract

Accumulation of amyloid-β (Aβ) in brain vessel walls, known as cerebral amyloid angiopathy (CAA), plays a key role in Alzheimer’s disease pathogenesis. CAA might result from impaired transport of Aβ out of the brain. Although the mechanisms underlying reduced Aβ transport are largely unknown, thickening of basement membrane extracellular matrix (ECM) is likely involved. Tissue transglutaminase (tTG) is an enzyme capable of modulating the ECM by covalently cross-linking ECM proteins. Recently, our group found that tTG and its cross-linking activity are associated with CAA pathology, suggesting a role for tTG in ECM modulation in CAA. Therefore, inhibition of tTG activity might be a promising novel therapeutic target to counteract CAA.
 
 
It is amazing what some doctors will charge.  When medicine became a huge business rather than a service, all the rest of us suffered. 

 

 


Serenoa
Posted: Friday, August 30, 2013 10:58 AM
Joined: 4/24/2012
Posts: 484


This is great info Lane! Thanks. I'm bookmarking links and making connections.

 

Yes, I had heard that Dr. Pearlmutter (he's in Naples/Ft. Myers, FL I think) was not afraid to try alternative, cutting edge therapies back when I was trying to get mom on Leukine. I'm guessing since his methods are outside of what the average doctor would do, that it may be a problem getting insurance to cover it. If he's really doing good work then the price would be worth it. But, it is a problem that the average doctor just relies on prescribing drugs, and won't even tell a patient to eat an avacado and go to the gym.


Serenoa
Posted: Friday, August 30, 2013 11:32 AM
Joined: 4/24/2012
Posts: 484


Here's another supporting article that I don't think has been posted yet.

 

 

International Journal of Alzheimer's Disease
Volume 2011 (2011), Article ID 865432, 7 pages
Transglutaminases in the Pathogenesis of Alzheimer's Disease and Other Neurodegenerative Diseases

 

RESULTS

Numerous scientific reports suggest that TG activity is involved in the pathogenesis of Alzheimer’s disease and other neurodegenerative diseases. To date, however, definitive experimental findings about the role of these enzymes in the development of these neurological diseases have not yet been obtained. Protein aggregates in affected brain regions are histopathological hallmarks of Alzheimer’s disease and many other  neurodegenerative diseases [27]. More than 20 years ago, Selkoe et al. [28]  suggested that TG activity might contribute to the formation of protein aggregates in AD brain. In support of this hypothesis, tau protein has been shown to be an excellent in vitro substrate of TGs [29–32], and GGEL cross-links have been found in the neurofibrillary tangles and paired helical filaments of AD brains [33, 34]. In addition to these experimental findings, it has been shown that TGs and transglutaminase-catalyzed cross-links colocalize with pathological lesions in Alzheimer’s disease brain [34–36].  Interestingly, a recent work showed the presence of bis γ-glutamyl putrescine in human CSF, which was increased in Huntington’s disease (HD) CSF [37]. These are important experimental data which demonstrate that protein/peptides cross-links and  protein/peptides cross-linking by polyamines do indeed occur in brain, and that these transglutaminase-catalyzed reaction products are increased in AD and HD brains. More recently, TG activity has been shown to induce amyloid β-protein oligomerization  and aggregation at physiologic levels in vitro

 


http://www.hindawi.com/journals/ijad/2011/865432/

 

 



Lane Simonian
Posted: Saturday, August 31, 2013 12:08 AM
Joined: 12/12/2011
Posts: 5001


This simple, clear abstract really ties things together.  Now what the doctor said before about the loss of endothelial nitric oxide being a potentially critical factor in Alzheimer's disease makes perfect sense. 

 

2007 Feb 20;581(4):702-6. Epub 2007 Jan 24.

TAT-BH4 counteracts Abeta toxicity on capillary endothelium.

Source

Department Molecular Biology, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy. cantara@unisi.it

Abstract

Oxidative stress is one of the factor contributing to blood brain barrier degeneration. This phenomenon is observed during pathological conditions such as Alzheimer's disease or cerebral amyloid angiopathy in which brain haemorrhages are very frequent. Both diseases are characterized by beta amyloid peptide deposition either in neurons or in vessels. Oxidative stress leads to impairment of mitochondrial functions and apoptotic cell death subsequent to caspases activation. In this paper we demonstrate that BH4 domain of Bcl-xl administrated to endothelial cells as the conjugated form with TAT peptide, reverts Abeta-induced apoptotic cell death by activating a survival programme which is Akt/endothelial nitric oxide synthase dependent.

 

http://www.ncbi.nlm.nih.gov/pubmed/17274989 

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1768213/ 

 

Thus evidence from various studies mentioned above suggests that peroxynitrite is a major mediator of vascular injury under diabetic conditions and indicates that effective neutralization of peroxynitrite formation can be beneficial in restoring NO bioavailability and vascular health. [in section 7 of article].

 

http://www.hindawi.com/journals/ijvm/2012/918267/ 

 

 

Either on its own or in conjunction with other inflammatory factors (such as high glucose levels), tissue transglutaminase likely plays an important role in Alzheimer's disease (thanks for the valuable article Serenoa and your comments). 

 

 

 


Lane Simonian
Posted: Saturday, August 31, 2013 9:45 AM
Joined: 12/12/2011
Posts: 5001


We may be very close to explaining the vascular dysfunction that often accompanies Alzheimer's disease.  Gp91ds-tat  inhibits  NADPH oxidase and thus the production of superoxide anions.  If you inhibit the production of superoxide anions you inhibit the formation of peroxynitrites and if you inhibit peroxynitrites you inhibit the oxidation of BH4 and if you inhibit the oxidation of BH4 you limit vascular dysfunction in Alzheimer's disease. 

 

 

NADPH Oxidase-Derived Reactive Oxygen Species Mediate

the Cerebrovascular Dysfunction Induced by the

Amyloid B Peptide

 

Laibaik Park,1 Josef Anrather,1 Ping Zhou,1 Kelly Frys,1 Rose Pitstick,3 Steven Younkin,2 George A. Carlson,3 and

Costantino Iadecola1

 

1Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, 2Mayo

Clinic Jacksonville, Jacksonville, Florida 32224, and 3McLaughlin Research Institute, Great Falls, Montana 59405

 

Overproduction of the amyloid (AB) peptide is a key factor in the pathogenesis of Alzheimer’s disease (AD), but the mechanisms of its

pathogenic effects have not been defined. Patients with AD have cerebrovascular alterations attributable to the deleterious effects of AB 

on cerebral blood vessels. We report here that NADPH oxidase, the major source of free radicals in blood vessels, is responsible for the

cerebrovascular dysregulation induced byAB. Thus, the free-radical production and the associated alterations in vasoregulation induced

by AB are abrogated by the NADPH oxidase peptide inhibitor gp91ds-tat and are not observed in mice lacking the catalytic subunit of

NADPHoxidase (gp91phox). Furthermore, oxidative stress and cerebrovascular dysfunction do not occur in transgenic mice overexpressing

the amyloid precursor protein but lacking gp91phox. The mechanisms by which NADPH oxidase-derived radicals mediate the cerebrovascular

dysfunction involve reduced bioavailability of nitric oxide. Thus, a gp91phox-containing NADPH oxidase is the critical link

between AB and cerebrovascular dysfunction, which may underlie the alteration in cerebral blood flow regulation observed in AD

patients.