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The Marshall Protocol Study Site > PROF. MARSHALL'S PERSPECTIVE > Prof. Marshall's Perspective > Alzheimers Amyloid protein is an Antimicrobial Peptide


Alzheimers Amyloid protein is an Antimicrobial Peptide
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Prof Trevor Marshall
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 Posted: Wed Mar 3rd, 2010 02:46

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As I read the latest article in PLOSone describing how Amyloid-beta protein, the supposed cause of Alzheimers, is an antimicrobial peptide of the innate immune system, related to LL-37 (Cathelicidin), I can't help but reflect how far the science has progressed these last few years.

Here is the Science Daily article:

http://www.sciencedaily.com/releases/2010/03/100302201656.htm

And here is the PLOSone article:

http://tinyurl.com/ydzs53p
"Now we need to figure out what is triggering the innate immune system, particularly as we age, and what genes control A-beta's role in the innate response," says Moir, who is an assistant professor of Neurology at Harvard Medical School (HMS). "If we can identify which pathogens are more likely to trigger A-beta plaque aggregation, we might develop ways to prevent or control that response, for example by immunization."
All you need is Google, Moir... Google (or PubMed)...
 
..Trevor..
 

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 Posted: Wed Mar 3rd, 2010 03:36

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WOW!

The inflammatory aspects of Chlamydia pneumoniae-induced brain infection.

http://www.ncbi.nlm.nih.gov/pubmed/20011709

 

Role of infection in the pathogenesis of Alzheimer's disease: implications for treatment.

http://www.ncbi.nlm.nih.gov/pubmed/19958038

 

Chronic inflammation and amyloidogenesis in Alzheimer's disease -- role of Spirochetes.

http://www.ncbi.nlm.nih.gov/pubmed/18487847

"Recent observations showed that bacteria, including spirochetes contain amyloidogenic proteins and also that Abeta deposition and tau phosphorylation can be induced in or in vivo following exposure to bacteria or LPS. Bacteria or their poorly degradable debris are powerful inflammatory cytokine inducers, activate complement, affect vascular permeability, generate nitric oxide and free radicals, induce apoptosis and are amyloidogenic. All these processes are involved in the pathogenesis of AD. Old and new observations, reviewed here, indicate that to consider the possibility that bacteria, including several types of spirochetes highly prevalent in the population at large or their persisting debris may initiate cascade of events leading to chronic inflammation and amyloid deposition in AD is important, as appropriate antibacterial and antiinflammatory therapy would be available to prevent dementia."


Reduction of vitamin D hormone receptor mRNA levels in Alzheimer as compared to Huntington hippocampus: correlation with calbindin-28k mRNA levels.

http://www.ncbi.nlm.nih.gov/pubmed/1317496

"These results show that in Alzheimer hippocampal CA1 cells, VDR mRNA pool size is downregulated"

 

Amyloid-beta peptide degradation in cell cultures by mycoplasma contaminants

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2527505/

Guess they wanna protect themself?

Last edited on Wed Mar 3rd, 2010 03:44 by Bane

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 Posted: Wed Mar 3rd, 2010 04:00

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This makes me think about the origin of Prion proteins. :)



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 Posted: Wed Mar 3rd, 2010 04:25

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Enhancing the Innate Immune System may help to protect brain agains Alzheimer.

http://www.sciencedaily.com/releases/2005/06/050612112041.htm

was published already in 2005.

Alex



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 Posted: Wed Mar 3rd, 2010 04:37

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1alpha,25-dihydroxyvitamin D3 interacts with curcuminoids to stimulate amyloid-beta clearance by macrophages of Alzheimer's disease patients.

http://www.ncbi.nlm.nih.gov/pubmed/19433889

"In silico, 1,25D3 showed preferential binding to the genomic pocket of the vitamin D receptor, whereas bisdemethoxycurcumin showed preference for the non-genomic pocket."

Comment from Trevor: These researchers have no credibility. They have not published a credible location or function of this "non-genomic binding pocket" and previous publications have dealt with the benefits of high-dose Vitamin D. Circumin actually binds well into the normal ligand binding domain.

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 Posted: Thu Mar 4th, 2010 01:09

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Wow.. indeed!  Thanks Dr Marshall for keeping us so well informed on these papers and new findings!

This interesting finding, that is totally consistent with Dr Marshall's research, hopefully means that perhaps mainstream medicine is getting closer to figuring out that PATHOGENS cause many of these neurodegenerative diseases!

It is not a large leap of faith, even for some of these stubborn researchers to make, to conclude that: if pathogens trigger the AMP's that then cause a neurodegenerative disease like Alzheimer's... the same mechanism could be the causal factor in many other neurodegenerative diseases... like ALS!!!

And it is tragic that these researchers are not building on the revolutionary findings of Dr Marshall along these same lines of research.  Like Trevor said ... all they need is Google for crying out loud! 

I certainly will pass this information on to my neurologist and get her opinion. 



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Bane
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 Posted: Thu Mar 4th, 2010 04:47

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Microglia Activation and Anti-inflammatory Regulation in Alzheimer's Disease.

http://www.ncbi.nlm.nih.gov/pubmed/20195797

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

Inflammatory regulators, including endogenous anti-inflammatory systems, can down-regulate inflammation thus providing negative feedback. Chronic inflammation can result from imbalance between levels of inflammatory mediators and regulators during immune responses. As a consequence, there are heightened inflammatory responses and irreversible tissue damage associated with many age-related chronic diseases. Alzheimer's disease (AD) brain is marked by prominent inflammatory features, in which microglial activation is the driving force for the elaboration of an inflammatory cascade. How the regulation of inflammation loses its effectiveness during AD pathogenesis remains largely unclear. In this article, we will first review current knowledge of microglial activation and its association with AD pathology. We then discuss four examples of anti-inflammatory systems that could play a role in regulating microglial activation: CD200/CD200 receptor, vitamin D receptor, peroxisome proliferator-activated receptors, and soluble receptor for advanced glycation end products. Through this, we hope to illustrate the diverse aspects of inflammatory regulatory systems in brain and neurodegenerative diseases such as AD. We also propose the importance of neuronal defense systems, because they are part of the integral inflammatory and anti-inflammatory systems. Augmenting the anti-inflammatory defenses of neurons can be included in the strategy for restoration of balanced immune responses during aging and neurodegenerative diseases.

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 Posted: Thu Mar 4th, 2010 11:56

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Independent component analysis of Alzheimer's DNA microarray gene expression data

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646728/

Significant genes found by ICA
 
"Even though the immune system tends to work less effectively in older adults than in younger ones, the elderly are prone to neuroinflammation. In fact, even though recent studies have indicated that certain aspects of the inflammatory response may have therapeutic potential [22-24], neuroinflammation is commonly believed to be a culprit in AD pathogenesis. Associated with this robust inflammatory response is the extracellular deposition of amyloid β-protein (Aβ) [25] that together are the characteristic pathological features of AD. are To validate the strong link between neuroinflammation and AD, we found that many inflammation-related genes are highly expressed, such as AMIGO2, BTG1, CD24, CD44, CDC42EP4, IFITM1, IFITM2, IRF7, FI44L, IL4R, IRAK1, NFKBIA, as Table 1 shows."
 
"Our ICA selected results exhibited NF-κB (NFKBIA) at a high expression in severe AD (see Table 1). NF-κB plays a key role in regulating the immune response to infection. Consistent with this role, incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development. NF-κB has also been implicated in processes of synaptic plasticity and memory. The NF-κB activation provides the potential link between inflammation and hyperplasia."

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 Posted: Thu Mar 4th, 2010 12:51

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Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806632/

Objective To investigate whether angiotensin receptor blockers protect against Alzheimer’s disease and dementia or reduce the progression of both diseases.

Conclusions Angiotensin receptor blockers are associated with a significant reduction in the incidence and progression of Alzheimer’s disease and dementia compared with angiotensin converting enzyme inhibitors or other cardiovascular drugs in a predominantly male population.




Last edited on Thu Mar 4th, 2010 12:55 by Bane

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 Posted: Thu Mar 4th, 2010 18:45

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Trevor said:
Circumin actually binds well into the normal ligand binding domain.
Do you know does it act as a VDR antagonist or if it could possibly activate the VDR?




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Prof Trevor Marshall
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 Posted: Thu Mar 4th, 2010 19:15

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I docked circumin in the VDR and it looked as though it could be an agonist - it certainly had high affinity for the binding pocket. I didn't have the time to do the molecular dynamics necessary to make sure it is an agonist. It didn't seem as active as Olmesartan, though.

..trevor..

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 Posted: Fri Mar 5th, 2010 03:04

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Curcumin: a novel nutritionally derived ligand of the vitamin D receptor with implications for colon cancer chemoprevention

http://tinyurl.com/yg9gtmw



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Prof Trevor Marshall
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 Posted: Fri Mar 5th, 2010 03:45

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The 'magic' of Olmesartan is not only its action in the VDR, but in a host of other receptors (and non-signaling proteins) as well. The sum total of which induces recovery from chronic disease :)
 

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 Posted: Fri Mar 5th, 2010 04:19

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So I wonder, why Amyloid-beta protein fails to eliminate infection ? It is not mis-folded protein after-all ?



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Bane
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 Posted: Fri Mar 5th, 2010 07:13

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wrotek wrote: So I wonder, why Amyloid-beta protein fails to eliminate infection ? It is not mis-folded protein after-all ?

Maybe the Microglia loses track of the amount of amyloid-beta present in the brain because of failing TLR2. Which in turn also means that the Microglia can't mount a complete attack against pathogens???

 

 

Activation of Toll-like Receptor 2 on Microglia Promotes Cell Uptake of Alzheimer Disease-associated Amyloid β Peptide

http://www.jbc.org/content/281/6/3651.long

"The human G-protein-coupled formyl peptide receptor-like 1 (FPRL1) and its mouse homologue mFPR2 mediate the chemotactic activity of a variety of polypeptides associated with inflammation and bacterial infection, including the 42-amino acid form of amyloid β peptide (Aβ42), a pathogenic factor in Alzheimer disease. Because mFPR2 was inducible in mouse microglial cells by proinflammatory stimulants, such as bacterial lipopolysaccharide, a ligand for the Toll-like receptor 4 (TLR4), we investigated the role of TLR2 in the regulation of mFPR2. We found that a TLR2 agonist, peptidoglycan (PGN) derived from Gram-positive bacterium Staphylococcus aureus, induced considerable mFpr2 mRNA expression in a mouse microglial cell line and primary microglial cells. This was associated with a markedly increased chemotaxis of the cells in response to mFPR2 agonist peptides. In addition, activation of TLR2 markedly enhanced mFPR2-mediated uptake of Aβ42 by microglia."

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

"The formyl peptide receptors (FPR) are a members of a class of G protein-coupled receptors involved in chemotaxis.[1][2] These receptors where originally identified by their ability to bind N-formyl peptides such as N-formylmethionine produced by the degradation of either bacterial or host cells.[3][4] Hence formyl peptide receptors are involved in mediating immune cell response to infection."


 

Toll-Like Receptor 2 Acts as a Natural Innate Immune Receptor to Clear Amyloid β1–42 and Delay the Cognitive Decline in a Mouse Model of Alzheimer's Disease

http://www.jneurosci.org/cgi/content/full/28/22/5784

"TLR2 deficiency accelerated spatial and contextual memory impairments, which correlated with increased levels of Aβ1–42 and transforming growth factor β1 in the brain."

 

Fibrillar Amyloid-β Peptides Activate Microglia via TLR2: Implications for Alzheimer’s Disease

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2701549/

"The present study underlines the importance of TLR2 in mediating Aβ peptide-induced activation of microglia. Fibrillar Aβ1–42 peptides induced the expression of inducible NO synthase, proinflammatory cytokines (TNF-α, IL-1β, and IL-6), and integrin markers (CD11b, CD11c, and CD68) in mouse primary microglia and BV-2 microglial cells. However, either antisense knockdown of TLR2 or functional blocking Abs against TLR2 suppressed Aβ1–42-induced expression of proinflammatory molecules and integrin markers in microglia. Aβ1–42 peptides were also unable to induce the expression of proinflammatory molecules and increase the expression of CD11b in microglia isolated from TLR2−/− mice. Finally, the inability of Aβ1–42 peptides to induce the expression of inducible NO synthase and to stimulate the expression of CD11b in vivo in the cortex of TLR2−/− mice highlights the importance of TLR2 in Aβ-induced microglial activation. In addition, ligation of TLR2 alone was also sufficient to induce microglial activation."

 

 

 


Last edited on Fri Mar 5th, 2010 11:24 by Bane

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 Posted: Fri Mar 5th, 2010 08:20

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The Lipoprotein Receptor LR11 Regulates Amyloid  Production and Amyloid Precursor Protein Traffic in Endosomal Compartments

http://www.jneurosci.org/cgi/content/full/26/5/1596

"Here, we show neuronal expression of the lipoprotein receptor LR11 in control brain in regions vulnerable to AD neuropathology and marked reduction of LR11 expression in these regions in AD brains before cell death." 

 

Last edited on Fri Mar 5th, 2010 08:20 by Bane

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 Posted: Wed Mar 10th, 2010 03:24

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Could Amyloid A be Antimicrobial??? http://en.wikipedia.org/wiki/Amyloid

 

Serum amyloid A regulates granulomatous inflammation in sarcoidosis through Toll-like receptor-2.

http://www.ncbi.nlm.nih.gov/pubmed/19910611

"Serum amyloid A activated NF-kappaB in Toll-like receptor-2-expressing human cell lines; regulated experimental Th1-mediated granulomatous inflammation through IFN-gamma, tumor necrosis factor, IL-10, and Toll-like receptor-2; and stimulated production of tumor necrosis factor, IL-10, and IL-18 in lung cells from patients with sarcoidosis, effects inhibited by blocking Toll-like receptor-2."

 

Serum amyloid A protein binds to outer membrane protein A of gram-negative bacteria.

http://www.jbc.org/content/280/19/18562.long

"Further studies will be needed to determine whether this interaction has a role in innate immunity."

 

Serum amyloid A is an innate immune opsonin for Gram-negative bacteria

http://bloodjournal.hematologylibrary.org/cgi/content/full/108/5/1751

"In this report we have shown that SAA not only binds to many Gram-negative bacteria but, when it has done so, can induce a number of responses from both macrophages and neutrophils, which are responsible for rapid killing of invading bacterial pathogens."

 

Comparison of serum amyloid A concentrations with those of C-reactive protein and procalcitonin in diagnosis and follow-up of neonatal sepsis in premature infants.

http://www.ncbi.nlm.nih.gov/pubmed/19078972

"SAA is an accurate and reliable marker for diagnosis and follow-up of neonatal sepsis. It is especially useful at the onset of inflammation for rapid diagnosis of neonatal sepsis and can be safely and accurately used in combination with other sepsis markers such as CRP and PCT in diagnosis and follow-up of neonatal sepsis in preterm infants."

 

Human Serum Amyloid A Protein Inhibits Hepatitis C Virus Entry into Cells

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1900255/

"Serum amyloid A (SAA) is an acute-phase protein induced by a variety of inflammatory stimuli, including bacterial and viral infections. SAA was recently found to function as an opsonin for gram-negative bacteria."

 

Serum amyloid A mediates human neutrophil production of reactive oxygen species through a receptor independent of formyl peptide receptor like-1

http://www.jleukbio.org/cgi/content/full/83/2/245

"Serum amyloid A (SAA) is one of the acute-phase reactants, a group of plasma proteins that increases immensely in concentration during microbial infections and inflammatory conditions, and a close relationship between SAA levels and disease activity in rheumatoid arthritis (RA) has been observed.

 

Mechanisms of the Hepatic Acute-Phase Response during Bacterial Pneumonia

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2687329/

"During bacterial pneumonia, APPs correlate with the severity of disease, serve as biomarkers, and are functionally significant."



 

Last edited on Wed Mar 10th, 2010 03:45 by Bane

wrotek
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 Posted: Wed Mar 10th, 2010 04:42

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Coffee increases SAA  http://findarticles.com/p/articles/mi_m0887/is_11_23/ai_n7578036/ Compared with coffee nondrinkers, men who consumed >200 mL coffee/d had 50% higher IL-6,30% higher CRP, 12% higher SAA, and 28% higher TNF- [alpha] concentrations and 3% higher WBC counts (all: P < 0.05). Women who consumed >200 mL coffee/d had 54% higher IL-6, 38% higher CRP, 28% higher SAA, and 28% higher TNF- [alpha] concentrations and 4% higher WBC counts (all: P < 0.05) than did non coffee drinkers.



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Bane
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 Posted: Wed Mar 10th, 2010 05:41

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wrotek wrote: Coffee increases SAA  http://findarticles.com/p/articles/mi_m0887/is_11_23/ai_n7578036/ Compared with coffee nondrinkers, men who consumed >200 mL coffee/d had 50% higher IL-6,30% higher CRP, 12% higher SAA, and 28% higher TNF- [alpha] concentrations and 3% higher WBC counts (all: P < 0.05). Women who consumed >200 mL coffee/d had 54% higher IL-6, 38% higher CRP, 28% higher SAA, and 28% higher TNF- [alpha] concentrations and 4% higher WBC counts (all: P < 0.05) than did non coffee drinkers.

 

I guess the question is, were they drinking coffee for it's immunosuppressive effects? Meaning the reason they had higher inflammatory markers wasn't because of drinking coffee, but that people that drink a lot of coffee happen to do so because their prone to TH1, maybe??;)

Associations between coffee consumption and inflammatory markers in healthy persons: the ATTICA study

http://www.ajcn.org/cgi/content/full/80/4/862#SEC2

Last edited on Wed Mar 10th, 2010 12:03 by Bane

wrotek
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 Posted: Fri Mar 12th, 2010 00:25

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http://iospress.metapress.com/content/k457101686r62685/
1α,25-dihydroxyvitamin D_{3} Interacts with Curcuminoids to Stimulate Amyloid-β Clearance by Macrophages of Alzheimer's Disease Patients I wonder what expresses beta amyloid, since vdr is blocked, it is something else right  ?

Bane, I think that coffee is immunosupressive and immune stimulating at the same time. There is coffeeforum where ppl express their experience with drinking coffee and when they quit, pain decreases in arthritics for example. But what good is inflammation if it is not directed into real threat, it only damages your body.



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