Chronic inflammation is getting a bad name for its presumed role in several diseases—and new research shows that its notoriety may be well deserved.
A team led by Jeffery W. Kelly, a chemistry professor at Scripps Research Institute, suggests that abnormal cholesterol and lipid metabolites produced as a result of inflammation bond with normal amyloid β peptides in the brain. These reactions increase the peptides' hydrophobicity, predisposing them to misfold. The misfolded peptides then aggregate into the neurotoxic fibrils characteristic of Alzheimer's disease [Proc. Natl. Acad. Sci. USA, published online March 15, http://www.pnas.org/cgi/doi/10.1073/pnas.0400924101].
The inflammatory process involves several types of cells and signaling compounds in a complicated cascade. In the peripheral nervous system, one control point for the cascade centers on the binding of acetylcholine to macrophages, which curtails the cells' inflammatory response. Last year, Kevin J. Tracey and colleagues at the North Shore Long Island Jewish Research Institute in Manhasset, N.Y., identified the binding site on the blood-borne macrophages as an 7 nicotinic acetylcholine receptor [Nature, 421, 384 (2003)].
New results from the University of South Florida (USF), Tampa, suggest that a similar control mechanism might exist in the brain. USF neuroscientists Jun Tan and R. Douglas Shytle and their colleagues show that the 7 receptor can be found on the brain's microglial cells, which mediate immune response in the central nervous system [J. Neurochem., published online March 8, http://www.blackwell-synergy.com/links/doi/10.1046/j.1471-4159.2004.02347.x].
Microglia in patients with diseases such as Alzheimer's and Parkinson's become excessively active, which "gives rise to persistent inflammation, resulting in exacerbation of neurodegeneration," the USF team hypothesizes.
Smoking appears to provide some protection against such diseases. The researchers believe binding of nicotine to the glial cells' 7 receptors suppresses their inflammatory activity. Thus, mimics of nicotine that avoid its side effects could potentially be used as preventatives for neurodegenerative diseases.
The work, which the authors concede is preliminary, "is very interesting and intriguing and should be followed up," says Jerrel L. Yakel, who studies acetylcholine receptors at the National Institute of Environmental Health Sciences.