Presents

DAILY DIGEST

REPORTING FROM ACTRIMS

Americas Committee for Treatment and Research in Multiple Sclerosis
West Palm Beach, Florida

SUNDAY, MARCH 1

Synaptic Loss is Critical Part of Grey Matter Pathology in Progressive Multiple Sclerosis

Martin Kerschensteiner (left), head of the Kerschensteiner Lab at Ludwig Maximilian University of Munich, Germany, posed with his fellow presenters Dorothy Schafer and Tarun Singhal following the session on CNS Cellular Networks in MS at ACTRIMs Forum, Saturday, February 29.WEST PALM BEACH, FL — Synapses play key roles in cellular function, as the chemical junctions through which neurons pass signals. However, we are only beginning to learn about the life and death of synapses in the context of multiple sclerosis (MS). Speaking at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum on Saturday, February 29, Martin Kerschensteiner, MD, discussed newer theories on synaptic loss in MS.

Dr. Kerschensteiner, Professor of Clinical Neuroimmunology and Neurosciences at the Ludwig Maximilian University of Munich (LMU) in Germany, agreed that our understanding of synaptic pathology in MS has just begun to evolve. "Traditionally, we have focused on white matter pathology, but MRI studies are telling us that an important part of the disease process that contributes to progressive pathology in MS actually happens in the grey matter," he said. "We now believe that neuronal damage in inflamed gray matter is actually initiated at the synapse."

Within the past decade, histopathological studies by Bruce Trapp and others have begun to reveal the importance of synaptic loss in MS brains. A subsequent study by Kerschensteiner and colleagues further indicates that such synapse loss does not seem to be restricted to the cortical lesions in the MS gray matter. "It was not surprising to see synapse loss present in the cortical regions that we classically associate with grey matter pathology in MS," Dr. Kerschensteiner said. "But we were surprised to see that the vast majority of neurons located outside of those classic areas also had synaptic loss. So this seemed to indicate relatively early and widespread changes in gray matter pathology that goes beyond what is happening if we looked only at the demyelinated regions."

At the Kerschensteiner Lab at LMU, the research team developed a mouse models of gray matter pathology in MS. "This model is based on just one of many hypotheses of how grey matter inflammation can be induced," Dr. Kerschensteiner said. In this case, the theory is that grey matter pathology is driven by proinflammatory cytokines (predominantly interferon gamma and TNF alpha) released by meningeal lymphocyte infiltrates. This drives the pathological activation of innate immune cells in the CNS such as microglia.  After introducing these cytokines in mice to initiate inflammation, the researchers observed widespread but reversible synaptic loss accompanied by neuronal hypoactivity. The studies showed that neuronal hypoactivity is transient, and neuronal activity as well as network activity can be restored.

The synapse seems to be a logical target for future treatment of progressive MS. One approach would be to broadly inhibit activation of the cells that are eating synapses during gray matter inflammation. In this case, the most likely culprits appear to be innate immune cells such as microglia and invading monocytes. Dr. Kerschensteiner believes that complement mediators, discussed in other sessions at the ACTRIMS Forum, are logical candidates. Synaptic loss is being recognized as a critical pathological aspect of other neurodegenerative diseases as well, including Alzheimer's disease (AD).

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By Katherine Wandersee, for the Consortium of Multiple Sclerosis Centers (CMSC)

 

© 2020, Consortium of Multiple Sclerosis Centers. Published by Delaware Media Group, LLC. All rights reserved. None of the contents may be reproduced in any form without prior written permission from the publisher. The opinions expressed in this publication are those of the presenters and do not necessarily reflect the opinions or recommendations of their affiliated institutions, the publisher, or Bristol-Myers Squibb.

Martin Kerschensteiner (left), head of the Kerschensteiner Lab at Ludwig Maximilian University of Munich, Germany, posed with his fellow presenters Dorothy Schafer and Tarun Singhal following the session on CNS Cellular Networks in MS at ACTRIMs Forum, Saturday, February 29.WEST PALM BEACH, FL — Synapses play key roles in cellular function, as the chemical junctions through which neurons pass signals. However, we are only beginning to learn about the life and death of synapses in the context of multiple sclerosis (MS). Speaking at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum on Saturday, February 29, Martin Kerschensteiner, MD, discussed newer theories on synaptic loss in MS.