Neural Stem Cells: A Possible Link Between Pathology and Clinical Manifestations of MS

Dr. Suh found that demyelination of nerve cells in the brain stalls the early stages of hippocampal neurogenesis and neuronal integration, and that these brain changes ultimately result in the cognitive impairment characteristic of multiple sclerosis.

01/31/2020

According to a new study published in the Journal of Neuroscience, Cleveland Clinic researchers have uncovered a possible mechanism of cognitive decline in multiple sclerosis (MS).

A progressive neurological disorder caused by demyelination of the central nervous system (deterioration of the protective coating that helps transmit signals between neurons), MS is frequently characterized by cognitive deficits related to memory, learning and information processing. While untangling a disease’s pathological and clinical manifestations can be challenging, understanding the interplay between the two can provide important insights about treatment or prevention strategies.

The researchers—led by Hoonkyo Suh, PhD, Department of Neurosciences—identified neural stem cells as a critical link between demyelination and cognitive impairment in MS. Their findings suggest that targeting hippocampal neurogenesis (the process by which neural stem cells differentiate into new adult-born neurons) may be a potentially viable and currently unexplored approach to mitigate or prevent MS-related cognitive impairment, which is estimated to affect as many as 70% of all patients living with the disease.

Here, in a preclinical model, Dr. Suh and his team—including co-author Bruce Trapp, PhD, Chair, Department of Neurosciences—induced hippocampal demyelination with a combination drug treatment (cuprizone + rapamycin) to simulate MS. When the drugs were removed, the hippocampus remyelinated. They compared brain pathologies before and after treatment to understand how demyelination affects the brain and may result in the cognitive impairments hallmark of MS.

They found that in the demyelinated brain, hippocampal neurogenesis and synaptic connectivity—indicators of neural development and integration, which are known to affect cognitive function—were severely inhibited compared to what was observed in the remyelinated brain.

About a decade ago, Dr. Suh made the discovery that hippocampal neurogenesis is a tightly regulated, multi-step process. To better understand what phase of neurogenesis is inhibited by demyelination, the researchers used advanced staining techniques. Staining revealed that during demyelination, neural stem cells became quiescent—like pressing the “pause” button on their replication process.

Taken together, these findings suggest that demyelination—as is characteristic in MS—stalls the early stages of hippocampal neurogenesis and neural circuit formation. The resultant reduction in the number of and connectivity between adult-born neurons is suspected to account for the impaired cognition experienced by so many MS patients.

Additional research will be necessary to further investigate these findings and validate in clinical models, but Dr. Suh says that it is very promising that neurogenesis and synaptic connectivity were restored in the absence of the demyelination-inducing drug treatment.

“Because we saw that neural stem cells essentially just freeze during demyelination—rather than die—and that they resume normal proliferation and differentiation to adult-born neurons, we think there is potential to target hippocampal neurogenesis as a strategy to restore cognitive function following MS onset,” commented Dr. Suh. “The team is excited to continue this line of investigation.”  

Hai Zhang, PhD, a postdoctoral research fellow previously in the Suh laboratory, is first author on the study, which was supported in part by the National Institute of Alcohol Abuse and Alcoholism and the National Institute of Neurological Disorders and Stroke (both parts of the National Institutes of Health), and well as the Hartwell Foundation.



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