Although amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is not usually thought of as an inflammatory disease, inflammatory responses contribute to its pathogenesis. Using the ALS mouse model B6SJL-Tg(SOD1*G93A)1Gur/J (002726), hereafter referred to as the SOD1*G93A mouse, a research team led by Howard Weiner, M.D., of the Department of Neurology, Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass., uncovered a key neuroinflammatory pathway involved in ALS (Butovsky et al. 2012). Furthermore, Weiner’s team used monoclonal antibodies to interfere with the pathway and mitigate ALS in the SOD1*G93A mouse. The team’s findings may help physicians identify early signs and stages of ALS and lead to novel ALS therapies.
ALS is a complex neuromuscular disease that usually attacks upper and lower motor neurons, degenerating large areas of the brain and spinal cord. It most commonly strikes people who are between 40 and 70 years old and affects as many as 30,000 Americans at any given time. Among its more famous victims are baseball players Lou Gehrig and Jim “Catfish” Hunter, physicist Stephen Hawkings, American folksinger Lead Belly, Senator Jacob Javits and Sesame Street creator David Niven.
An early symptom in 50 percent of ALS victims is weakness in a hand, foot, arm or leg. Other early symptoms include muscle weakness, slurred speech, difficulty swallowing and difficulty walking. There are currently no therapies or cure for ALS (The ALS Association).
Studying inflammatory responses in neurodegenerative diseases like ALS had been hampered by researchers’ inability to distinguish the macrophages (monocytes) that infiltrate the central nervous system from those that reside there – the microglia. The Weiner team found a differentiating marker: whereas the infiltrating monocytes express Ly6C, the resident microglia express CD39. Weiner and his colleagues used these differentiating markers to dissect a key ALS neuroinflammatory pathway in the SOD1*G93A mouse. Their salient findings are summarized below.
In summary, Weiner and his colleagues demonstrated that inflammatory responses contribute to motor neuron degeneration in ALS and suggest that targeting inflammatory splenic monocytes with mAbs can mitigate ALS. Their finding that splenic monocytes exhibit an inflammatory signature two months before disease onset suggests that inflammatory profiles could be used to detect early signs or identify disease stages of ALS.