Diet Friendly Fast Food

A recent review article on brain lipid metabolism discussed the results obtained by looking at how the major omega-6 fatty acid, arachidonic acid is imported and used in brain tissue. Arachidonic acid conversion to inflammatory prostaglandins was monitored by extracting lipids from rat brains after a variety of treatments. Similarly, isotopes (13C) of fatty acids were imaged by PET scans in patients treated for Alzheimer’s, bipolar disorder and Parkinson’s disease.

The major findings on brain arachidonic acid (AA, omega-6) and docosahexaenoic acid (DHA, omega-3) are:

• Ca. 5% of daily dietary AA and DHA are converted to make prostaglandins in the brain. Converted AA and DHA are rapidly replaced by serum AA and DHA.
• Brain DHA and AA metabolisms are independent.
• AA and DHA are rapidly circulated into phospholipids (R2 on the diagram) on the endoplasmic reticulum, move to the cytoplasmic membrane (see diagram, gray and white strands) removed by phospholipase A2 in synapses, converted to prostaglandins, leukotrienes, etc., or recycled to phospholipids. Enzymes that catalyze these reactions are usually different for DHA and for AA.
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• Drugs used to treat bipolar disorder (lithium, carbamazepine, valproic acid, lamotrigine) lower AA conversion in rats, but do not affect DHA conversion.
• Experimentally induced brain inflammation or neurotoxicity increases AA conversion, but not DHA conversion to prostaglandins.
• An omega-3 fatty acid deficient diet also increases AA, but not DHA conversion.
• More AA is converted in Alzheimer’s patients. This is consistent with increased inflammation and neurotoxicity in postmortem examinations.
• Mice that have been genetically manipulated to eliminate alpha-synuclein, a protein implicated in Parkinson’s disease, also show an increase in AA conversion and a decrease in DHA conversion.

Interpretation: Inflammation in the brain is separate from the rest of the body, but is the foundation of many brain disorders, including Alzheimer’s disease, bipolar disorder and Parkinson’s disease. In these disorders, arachidonic acid is rapidly converted into inflammatory prostaglandins and leukotrienes. Drugs that reduce symptoms, reduce AA conversion.

A diet rich in omega-3 DHA and reduced omega-6 arachidonic acid reduces the symptoms of these diseases -- an anti-inflammatory diet and lifestyle should be the first line of defense against brain/mental disorders.

reference:
Rapoport SI. 2008. Brain arachidonic and docosahexaenoic acid cascades are selectively altered by drugs, diet and disease. Prostaglandins Leukot Essent Fatty Acids. Oct 28. [Epub ahead of print]

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 Alzheimers 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.