Researchers identified a new mechanism in the progression of multiple sclerosis (MS) that might explain the cognitive impairment and decline observed in these patients — a decline not directly associated with disease’s hallmarks of motor control loss, and one not currently addressed by the immunosuppressive drugs used to treat MS.
“For too long, MS has been characterized as a disease that impairs people’s mobility, speech, or vision,” Dr. Harris Gelbard, director of the Center for Neural Development and Disease at the University of Rochester Medical Center (URMC) and senior study author, said in a press release. “However, the aspect of the disease that many patients complain has the greatest impact on their quality of life is the loss of cognitive independence.”
In MS, cells of the immune system attack the central nervous system (CNS), namely myelin, the element that covers and protects nerve cells, and the nerve fibers themselves. CNS inflammation, demyelination, and axon loss are all hallmarks of the disease, which is mostly associated with motor and sensory symptoms. A large percentage of the MS patient population also experience some level of cognitive problems, such as memory loss and difficulty processing information. Because such cognitive impairment is not prevented through current therapies targeting immune system overactivation and myelin damage, the researchers theorized that additional damage was happening to CNS neurons located outside those brain areas known to be affected by myelin loss.
The researchers investigated the brains of experimental autoimmune encephalomyelitis (EAE) mice, a commonly used model of human MS, and found synapse damage in an area not associated with motor control, the hippocampus. They determined that this damage could be attributed to microglia, cells that play an active role in the defense of neurons against infection and in the maintenance of functional synapses.
As a result of the immune system’s overactivation, microglia cells in MS patients switch from their normal function to an exacerbated pro-inflammatory state, causing the release of high levels of a platelet-activating factor (PAF), which in turn destroys the receiving end of the synapse. More immune cells and microglia rush to the site of injury and trigger, in a continuous loop, a cycle of synaptic destruction.
“This study identifies for the first time a new disease mechanism in MS which causes damage to neurons independent of the loss of white matter and demyelination that is the hallmark of the disease. This damage represents another component of the disease, and one that is not prevented by the current immunosuppressive drugs employed to treat MS,” said Dr. Matthew Bellizzi, the study’s lead author.
The researchers believe this self-perpetuating mechanism is responsible for the cognitive damage in MS, and are investigating drugs that suppress the signaling pathways that lead to nerve cells and microglia overactivation, including a drug being investigated to treat HIV-associated neurological disorders.
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