Anti-Inflammatory Diet

All health care starts with diet. My recommendations for a healthy diet are here:
Anti-Inflammatory Diet and Lifestyle.
There are over 190 articles on diet, inflammation and disease on this blog
(find topics using search [upper left] or index [lower right]), and
more articles by Prof. Ayers on Suite101 .

Friday, March 19, 2010

Rosacea: Alzheimer’s of the Face

Is Rosacea Caused by Amyloid LL-37, as Alzheimer’s Is Caused by Anti-microbial Abeta?
A recent article in PLoS One (Thanks Daniel!) suggests that the amyloid beta (Abeta) proteins that aggregate to form fibrous plaques in the brain tissue of Alzheimer victims, function as typical defensive anti-microbial peptides (AMPs), similar to the LL-37 cathelicidin implicated in facial tissue in rosacea.  The structural and functional similarities of Abeta and LL-37 suggest to me that Alzheimer’s and rosacea may also be similar in initiation and treatment.  Let’s compare amyloids and AMPs.

[The figure shows a model protein (from ref.) used to examine stain binding to amyloids.  The stains appear to bind to aromatic amino acids spaced evenly between adjacent proteins, but adjacent basic amino acids (blue) are spaced the same way and provide sites for heparin binding.]

Amyloids:
  • Amyloid proteins/peptides align into stacks and fibers
  • Stacked beta sheets bind amyloid stains: Congo Red, Thioflavin-T
  • Fibers form on anionic polymers: heparin, DNA
  • Short amyloid stacks are toxic to cells
  • Proteases produce multiple sizes of amyloid peptides

Anti-microbial Peptides:
  • AMPS typically contain heparin-binding domains -- basic peptides/ plus charge
  • Some AMPs, e.g. LL-37, form fibers on DNA, heparin (stain with amyloid stains)
  • Toxic to cell membranes
  • Kallikrein stimulated by gut flora migrates to face and clips LL-37 to a smaller peptide that binds to host DNA and stimulates the TLR receptor to produce inflammation
  • Stomach pepsin hydrolyzes dietary proteins into anti-microbial peptides (heparin is secreted by mast cells onto to the intestinal surface to protect from any amyloid-like effects)
  • Defensins, cathelicidins and other AMPs are under transcriptional control of vitamin D receptor

Abeta Is Anti-microbial Like LL-37

Amyloid beta is the well-known source of the fibrous plaques forming brain lesions in Alzheimer’s disease.  The normal function of Abeta has not been firmly established.  The recent article shows data to support Abeta as an anti-microbial peptide comparable to LL-37 against several pathogenic bacteria and yeast.  Knock-out mice deprived of a gene corresponding to Abeta are susceptible to bacterial infections.  The anti-microbial activity present in extracts from Alzheimer’s disease brains was inactivated by anti-Abeta antibodies.

Implications of Abeta as an AMP Like LL-37

The similarities between AMPs and amyloid peptides suggest some implications for both Alzheimer’s disease and rosacea.  Vitamin D is a hormone that binds to a cytoplasmic receptor and the vitD/receptor complex then acts as a transcription factor that controls the expression of defensins in the intestines, LL-37 in facial skin and perhaps Abeta in brains.

Amyloids form fibers on a scaffolding of heparan sulfate (HS).  There is usually an excess of HS on the surface of cells and the HS is rapidly recycled back into cells.  During inflammation, mast cells release heparin, short fragments of HS, that should also inhibit amyloid fiber formation on HS.   Chronic inflammation, however, reduces HS production and may set the stage for amyloid fiber formation.  HS metabolism of the brain may be vitally important to the development of Alzheimer’s disease, especially since the increasing chronic inflammation of aging people should deplete brain HS.

LL-37 forms complexes with DNA from damaged host cells in rosacea skin.  The LL-37/DNA complexes trigger TLRs and inflammation.  LL-37 may normally bind to cell surface HS and chronic inflammation of the skin may cause the shift to pathogenic autoinflammation.  Topical application or perhaps low dose IV heparin may be effective in disrupting the autoinflammation due to LL-37.  Part of the toxicity of LL-37 in the skin may be due to amyloid like structures that could form with inadequate HS and overabundant LL-37 production.  Vitamin D metabolism should also be very important, since LL-37 synthesis is controlled by vitamin D.  This is consistent with the benefits that some rosaceans observe with high doses of vitamin D3 supplements.

references:
Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, Hyman B, Burton MA, Goldstein LE, Duong S, Tanzi RE, Moir RD.  The Alzheimer's disease-associated amyloid beta-protein is an antimicrobial peptide.  PLoS One. 2010 Mar 3;5(3):e9505.

Abedini A, Tracz SM, Cho JH, Raleigh DP.  Characterization of the heparin binding site in the N-terminus of human pro-islet amyloid polypeptide: implications for amyloid formation.  Biochemistry. 2006 Aug 1;45(30):9228-37.

Biancalana M, Makabe K, Koide A, Koide S. Molecular mechanism of thioflavin-T binding to the surface of beta-rich peptide self-assemblies.  J Mol Biol. 2009 Jan 30;385(4):1052-63. Epub 2008 Nov 14.

13 comments:

caphuff said...

Doc, thanks for this fascinating post.

I have been working on the wife to start supplementing with Vitamin D and otherwise reduce refined carbs and sugar, etc. So far she has noticed improvements, not so much in the rosacea but in the interstitial cystitis that she has also suffered from for over 10 years. Interesting, no?

I will now try to get her to ask the dermatologist for a prescription for topical heparin as well.

Dr. Art Ayers said...

Caphuff,
It is not surprising that interstitial cyctitis responds to a general anti-inflammatory diet. IC is typically diagnosed by exclusion and is a disruption of the normal development of the lining of the bladder by inflammation. That makes it a cousin of inflammatory diseases of the gut and skin. All are based on chronic inflammation that may be based on numerous sources of diet. Gluten intolerance, celiac, is a major initiator of IC. Eliminating grains is typically a big help. Numerous food allergies also initiated by chronic dietary inflammation, then lead to IC. That explains the food triggers for IC.

IC can be considered to be rosacea of the bladder. As such, in many cases, I would expect gut flora and gut based irritation/leakiness to be big contributors. I would also expect some people with IC to respond favorably to the PEG used in total bowel irrigations prior to colonoscopy, since that strips gut biofilms. Likewise, the experiment that I did with the Eades Cure diet, would also be expected to eliminate IC in some people, just by changing gut flora.

It seems to me that your wife is gluten intolerant, and that is the source of most of her problems. Eliminate grain, starch, sugar and vegetable oils from the family diet for a month. Supplement with vitD3 and a half dozen fish oil capsules per day. You will be surprised how many inflammation-based symptoms disappear.

A castor oil pack applied to the lower belly may also help to decrease inflammation/pain in the lower abdomen. It probably works via vagal stimulation. Also try the vagal stimulation exercises that I have referenced in this blog. They are quite useful for treating inflammation.

Make sure that you don't have any dental sources of inflammation.

You might look for Lipactin as an OTC form of topical heparin.

Good luck and let me know how your experiments turn out.

caphuff said...

wow, thanks for the detailed response and recommendations!

I will print it out and show it to my wife. What you say makes perfect sense to me. Various IC food triggers have been recurring phenomena. Diagnosis of IC by exclusion is what she went through years ago, with Dr. Philip Hanno.

I think your characteriation of IC as rosacea of the bladder has a lot of clarifying force and certainly ties things together. Thanks again. I will keep you posted.

westie said...

Hello Art!

You wrote that "PEG strips gut biofilms". Are you referring to macrocol (polyethylene glycol)?

I'd love to hear more about that. How PEG could effect gut microbiota?

Dr. Art Ayers said...

Westie,
Search this site (Google upper left) for PEG.

When I talk about PEG for biofilm stripping, what I usually mean is that people with biofilm-based symptoms/diseases usually see relief if they have a colonoscopy that requires total bowel irrigation with PEG. The polyethylene glycol disrupts the polysaccharide matrix that holds biofilms together, so the TBI also strips off lots of biofilms that are disrupting the normal function of the gut in immunity (controlling development of the immune system cells that predominantly reside in the lining of the gut).

Some laxatives also use PEG and would be potentially useful for biofilm stripping. I don't think that it makes sense to continually try to destabilize biofilms, because some of the biofilms are needed for normal gut/immune function. Also it is important to try to establish a history of normal bowel function and healthy gut flora prior to TBI, otherwise the pathogenic status quo will just return.

Thanks for the comments.

Anonymous said...

Dear doctor,

I have long suspected that there might be a connection between the chronic inflammation of rosacea and the brain inflammation of Alzheimer's. Tonight I typed in "Alzheimer's" and "rosacea" in my browser, hoping that my search wouldn't yield anything. Instead, I was dumbfounded to see your article (and to find excerpts on the topic from medical journal articles dating back to the 1950s!)

Although I am a health and medical editor, I have never run across this research.

Although I felt vindicated (having had some friends laugh about my theory), I also feel somewhat frightened. Both my healthy, fit, loving, and extremely intelligent parents developed Alzheimer's at relatively early ages, with my father dying of it in his sixties. And they both had rosacea, as do I.
Looking over my father's medical records, I was also surprised to find that at one point he had a cholesterol level of 360 (!)

I have small children, so my biggest fear is that I will develop Alzheimer's while they are still young. Also, because I have children, I can't respond to a diagnosis the way my brother and I once planned (suicide). I will work my way through your fascinating site with great interest.

Thanks again for your post.

Diana

Dr. Art Ayers said...

Diana,
The relationship between rosacea and Alzheimer's that I focus on is only to say that both involve anti-microbial proteins, LL-37 and Abeta, that stackup on heparin to make amyloids. This does not say that rosacea can lead to Alzheimer's nor that there is a genetic predisposition shared by both.

I do, however, suggest that these amyloid diseases and many other degenerative and autoimmune diseases share a foundation of predisposing chronic inflammation. In many cases that inflammation is dietary and disruption of normal gut and flora interactions contributes to the disease progression. Chronic use of antibiotics should guarantee disease development by persistent disruption of gut flora and associated disruption of the immune system.

I believe that these degenerative diseases can be avoided by healing the gut via an anti-inflammatory diet and lifestyle. I doubt that you inherited a predisposition to these diseases, but rather your family had common eating habits that led to their diseases.

Change your diet and change your destiny.

Thanks for your comments and I hope you enjoy my other 160 articles. Ask questions if you need clarification or you would like to discuss a new topic.

Anonymous said...

Doctor,

Thank you so much for your prompt and reassuring post! I am intrigued by the idea that our family had commmon eating patterns that may have contributed to Alzheimer's and rosacea.

In many ways, my parents were far ahead of their time in terms of nutrition. My father had a flourishing organic garden, blueberry bushes, strawberries, watermelons, and fruit trees, and we probably had more than 12 servings of vegetables and fruit a day. We ate whole grains, drank iced tea, never had chips or soda, and almost never ate out. But we rarely ate fish and my father did love ice cream, sometimes eating two or more bowls of it a day. In my early years, before my mother became interested in nutrition, we also had a fair amount of fried chicken and other fried foods (I'm from the south).

My father's side of the family has had several cases of Alzheimer's, my mother's, none except for her. She did have hormone therapy for many years. And all of us had a lot of antibiotics for bronchitis, pneumonia, and other problems.

I can't wait to read your advice on the anti-inflammatory diet. Do you think that more fish and omega-3s is a good idea?

Thanks again,

Diana

Dr. Art Ayers said...

Diana,
You have an interesting and progressive diet background. As is obvious from my articles, I focus on dietary sources of inflammation. That is where I look first and then I check for other common sources, such as dental infections or gut dysbiosis (lack of functional gut flora) as a result of antibiotics.

Your diet was great for its time, but leans towards the medical misinformation of the time. I suggest that your diet was relatively low in saturated fats, high in omega-6 vegetable oils, low in omega-3s, high in grains/starch.

I am now leaning toward veggies as a source of prebiotic polysaccharides and immunomodulatory phytochemicals, rather than emphasizing anti-oxidant properties which merely reflect the chemical categories of the molecules. So veggies are great, but for different reasons.

Fruits are good for phytochemicals, but bad as juices rich in inflammatory fructose.

I think that ice cream should be a food group. The saturated fat is healthy as a source of calories, but the sugar is very bad. We need to change our taste expectations, but that would just change ice cream into full fat frozen yogurt. That does sound very good. Pectin and inulin could also be added as thickeners and perhaps probiotic bacteria could survive the freezing process.

Grains are bad for inflammatory starch that feeds pathogenic biofilms and contains gluten that disrupts normal gut immune development in most people. Grains do promote gut bacteria and increase transit through the gut.

I think that with your history, you should get your serum vitD checked and keep it over 70 nl/ml, eliminate vegetable oils, use olive oil/butter/coconut oil, eliminate grains and eat meat/fish/veggies. Most calories should be from saturated fats rather than starch/sugar. That is just a tasty high fat/low carb diet that is easy and flexible. Whole fruits are fine. Occasional baked goods, pasta, etc. are no big deal, since your gut flora can adjust. Fish oil capsules can be added to eliminate any symptoms of inflammation until the source is found and eliminated.

I suspect that the major problem in your family has been the antibiotic use that has led to gut flora problems. A typical symptom would be constipation, which is a gut flora deficiency. Probiotics, prebiotics, pectin- and inulin-rich veggies should improve gut flora. Enjoy herbs and spices.

Thanks for the comments.

Anonymous said...

My 2006 publication (excerpt below) explicitly described Aβ as an antimicrobial peptide based on its multiple similarities to melittin.

In addition, the described antimicrobial action was explicitly cited as a basis for Aβ to be considered a component of the innate immune system, likely as a rapid response to infections by enveloped viruses such as HSV.

Excerpt from Kammerman et al., 2006:

"Numerous groups have reported that Aβ42 can disrupt lipid membranes by creating pore-like holes (ion channels) within the membranes. This property of Aβ42 appears to be related to an antimicrobial function; nature is replete with examples of peptide antimicrobials that effect their function through membrane disruption. In fact, some of these peptides show strong activity against HSV-1. For example, melittin, which has an α-helical amphipathic structure similar to Aβ42, has anti-HSV activity. We assert that β amyloid, by virtue of its similar molecular shape and size, is a peptide antimicrobial component of the innate immune system which can neutralize enveloped viruses such as HSV-1. We contend accordingly that ion-channel pore formation in the HSV-1 envelope generated by Aβ42 is virucidal."

References:
Kammerman EM, Neumann DM, Ball MJ, Lukiw W, Hill JM. Senile plaques in Alzheimer's diseased brains: possible association of beta-amyloid with herpes simplex virus type 1 (HSV-1) L-particles. Med Hypotheses. 2006;66(2):294-9.

Dr. Art Ayers said...

Anon,

People don't pay enough attention to theoretical perspectives, such as those found in Medical Hypotheses. I wish that I had seen your article earlier. Thanks for bringing it to my attention.

Using antimicrobial peptides to attack enveloped viruses is an interesting application of these peptides, which more typically have a series of hydrophobic amino acids with embedded basic amino acids. The AB42 is unusual in having fewer basic amino acids.

It would make sense that the AB32 would stack up on a scaffold of nucleic acid and or heparan sulfate. If fact the higher charge of the heparan sulfate may lead to displacement of the viral nucleic acid that may initially help to orient and stack the AB42 into fibers.

Viral infections may also play a role in rosacea and may lay the foundation for persistent inflammation. It is also interesting that heparin is effective in providing protection against herpes infections. That is why I would like someone to test the cold sore medication, Lipactin, which contains heparin and zinc, on rosacea.

Thanks for your comments.

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Anonymous said...

Acyclovir or Abeta42 peptides attenuate HSV-1-induced miRNA-146a levels in human primary brain cells

http://journals.lww.com/neuroreport/Abstract/publishahead/Acyclovir_or_A_beta_42_peptides_attenuate.99729.aspx

Abstract
Human brains harbor herpes simplex virus type-1 (HSV-1) DNA, which normally remains quiescent throughout many decades of life. HSV-1 is associated with viral encephalopathy and with the amyloid beta 42 (A[beta]42) peptide-enriched lesions that characterize Alzheimer's disease neuropathology. Here we report that infection of human neuronal-glial cells in primary co-culture with HSV-1 induces an irregular hypertrophy of human neuronal-glial cell bodies, an induction of HSV-1 DNA polymerase, and an up-regulation of micro-RNA-146a associated with altered innate-immune responses. Presence of the antiviral acyclovir or soluble A[beta]42 peptide significantly attenuated these neuropathological responses. The inhibitory effects of A[beta]42 peptide were also observed in an HSV-1-infected CV-1 cell-based viral plaque assay. The results suggest that soluble A[beta]42 peptide can invoke non-pathological and anti-viral effects through inactivation of an HSV-1 challenge to human brain cells by simple viral sequestration, viral destruction, or by complex neurogenetic mechanisms.