Open Up Your Brain

The brain is fed and oxygenated by capillaries that penetrate its grey matter, but the cells and proteins of the blood are kept separated from the brain by the cells and matrix of the vessel walls, the blood brain barrier (BBB). That barrier can be breached by inflammation that lowers the heparan sulfate composition and stretches the matrix.

The blood can be considered a large organ with liquid surrounding the cells of the tissue instead of extracellular matrix composed of proteins and polysaccharides. Organs are typically surrounded by a basement membrane made of laminin, entactin (nidogen), collagen and perlecan (a heparan sulfate proteoglycan). These components are secreted by the adjacent cells, and the proteins and polysaccharide (heparan sulfate) bind to each other in multiple ways and hold the tissue together. The cells lining blood vessels, endothelial cells, are connected to each other by tight junctions and the space between the cells is filled with the extracellular matrix of the endothelial cells, the equivalent of the basement membrane of the blood.

Inflammation leads to an alteration in the structure of blood vessels that produces the gross symptoms of inflammation: swelling, reddening, warmth and pain -- the blood vessels dilate or stretch. Persistent or chronic inflammation of vessels can lead to changes in the composition of basement membranes and one notable change is a decrease in the heparan sulfate proteoglycan.

In my own research on the molecular impact of inflammation, one of my students, April Reimers, induced inflammation in cultures of cartilage secreting cells, chondrocytes, using a glucan (similar to the glucan elicitor that I used thirty years earlier to stimulate disease resistance in plants.) She used real time reverse transcriptase PCR to follow the expression of the genes involved. The inflammation transcription factor, NFkB, was turned on (as judged by a compensating induction of its inhibitor IkB) and proteins and enzymes involved in the expression of heparan sulfate proteoglycans were shut down. Our interpretation was that inflammation reduces some heparan sulfate proteoglycans. Since there are at least a dozen different HSPGs with different patterns of expression, we would expect there to be some exceptions from the general suppression caused by inflammation.

Inflammation caused by many different diseases opens up capillaries to provide access of the immune system to damaged tissue. Breakdown of the integrity of an endothelial barrier with an inflammatory decrease in HSPG in kidneys is observed as proteinuria (loss of protein into the urine) due to high blood sugar of diabetes. Breakdown of the capillaries also disrupts blood flow to extremities and is responsible for amputations in diabetics with poor control of blood sugar. Inflammation of intestinal blood vessels and HSPG reduction occurs in protein lossing enteropathy (loss of blood protein into the lumen of the intestines) as a result of heart reconstruction to repair congenital structural defects. The same thing happens to the BBB when vessels of the brain experience inflammation.

Breaching of the BBB is an essential initiating event in many diseases of the brain. Subsequent flareups of symptoms may signal repeat compromise of the barrier between the blood and the brain. The reduction of the barrier, including a decrease in HSPG, permits transit of antibodies, other proteins, e.g. the beta amyloid peptides of Alzheimer’s disease, and lymphocytes from the blood into the brain. The region of the brain that is inflamed and the nature of the interaction between the blood components and the brain determine the symptoms. Examples would be the autoimmune attack on the myelin sheath of nerves in multiple sclerosis and the aggregation of fibers of beta amyloid peptides with heparan sulfate on the surface of neurons in Alzheimer’s disease.

Shutting the blood brain barrier would seem to be the first step in disease treatment, but in some cases, the BBB must remain breached for medication to reach the brain -- the BBB is also a barrier to drugs. If the BBB is to be repaired, then inflammation must be stopped. In most cases, this is accomplished by anti-inflammatory drugs. In some cases, such as protein lossing enteropathy, heparin therapy can reverse symptoms. A very effective supplement to reduce chronic or in some cases acute inflammation is an anti-inflammatory diet. The components of these diets are discussed elsewhere on this blog. These diets have been used effectively in the treatment of MS, Alzheimer’s and many other degenerative and autoimmune diseases.