Alzheimer's treatment with anti-inflammatory protein drug

[susato]

The cytokine Tumor Necrosis Factor (TNF) is a potent pro-inflammatory agent secreted by immune system cells (white blood cells). It attracts other immune cells to the area where it's released, and also makes immune cells more aggressive in fighting "invaders" like bacteria and even cancer cells.

The downside of TNF is that it is present in many autoimmune diseases and in conditions causing chronic pain. TNF also appears to be involved in regulating nerve cell signaling in the brain. It's known that Alzheimer's patients have extremely high levels of TNF in their brain and spinal fluid.

So if you could capture TNF in the body before it binds to other immune cells, you could reduce inflammation in chronic spinal pain, fight autoimmune disease like psoriasis and rheumatoid arthritis and maybe improve the condition of Alzheimer's patients -- at the price of making the immune system less responsive to infection and cancer. The body makes its own soluble "TNF inhibitors", molecules which catch and bind TNF, but they are made at a low level and break down rapidly in the body.

A new class of drugs is the "fusion proteins" made by recombinant DNA methods, which patch together fragments of two or more different proteins into a new protein which combines the biological effects of both. One of these, etanercept, combines a binding site for TNF and the constant (Fc) region of an antibody. It acts like a soluble TNF inhibitor but has a much longer lifetime. Since it's a protein, it can't be taken by mouth but must be injected, ideally into the area of the body where it is to be used (e.g. the spinal fluid for nerve pain in the back) so that it doesn't go off into other parts of the body and suppress desired TNF activity there.

Here are two articles (free full text) about using etanercept to treat Alzheimer's - Very interesting! The first one is a case report, fascinating and even dramatic! The second one is a small pilot study with similar positive results.

http://www.jneuroinflammation.com/content/5/1/2

http://www.pubmedcentral.nih.gov/articl ... d=16926764

How is this related to F@h? Proteins begin to fold "locally" in small regions along the length of the amino acid chain, but after this initial step, long distance interactions become important and the entire protein condenses into shape together. Nothing guarantees that a fusion protein will fold properly into separately active domains - after all, the parts may originate from DNA of very different organisms. The two ends may get tangled with each other, or pieces of protein optimized by evolution to fold in very different environments (temperature, pH, salt concentration) may not fold well at the conditions inside the cell where they are produced. A possible new application for F@H is to help design fusion proteins so that each portion of the protein folds rapidly into its proper active conformation and remains stable in that shape.