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Aug 7, 2012

A Surprising New Target for ALS

  • Scientists have identified a role for inflammatory monocytes in the progression of amyotrophic lateral sclerosis (ALS), indicating that these immune cells may represent a therapeutic target. ALS is a progressive disease characterized by the degeneration of motor neurons. Although not considered primarily an inflammatory or immune-mediated disease, a Harvard Medical School team headed by researchers at Brigham and Women’s Hospital has now shown that inflammatory monocytes are activated and recruited to the spinal cord (but not the brain) of ALS patients, and that this recruitment is associated with neuronal loss.

    Reporting in the Journal of Clinical Investigation, Howard L. Weiner, M.D., and colleagues say their initial studies in the SOD1 mouse model of ALS showed that months before the disease becomes manifest, splenic monocytes begin to take on an inflammatory phenotype and demonstrate a unique, ALS-specific gene expression and miRNA expression profile. Then, at disease onset, increased production of CCL2 by microglia attracted monocytes to infiltrate the spinal cord. Notably, the team demonstrated that treating animals with an antibody that inhibits activity of the monocytes led to far fewer of these activated inflammatory cells entering the spinal cord, which resulted in significant reductions in nerve cell loss, as well as increased survival.

    Importantly, CD14+CD16– peripheral monocytes in human ALS patients (which are analogous to the infiltrating monocytes identified in the SOD1 mice) were found to exhibit ALS-specific gene and microRNA expression signatures that were similar to those in the mouse model. This indicates that a direct link exists between the murine and human disease, the investigators point out.

    And most notably, the ALS-specific miRNA profile in human patients could even be used to distinguish between ALS and other neuroinflammatory diseases such as multiple sclerosis. “Although we found broad similarities between the miRNA and inflammatory gene patterns in monocytes from MS and ALS patients, we identified unique miRNA and gene profiles in the blood of ALS patients,” the authors write. “Thus, the profile of monocytes in ALS patients may serve as a biomarker for disease stage or progression.” Dr. Weiner et al describe their findings in a paper titled “Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS.”

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