May 25, 2022
Mayo Clinic researchers have demonstrated that normalizing enzyme levels disrupted by a high-fat diet can lead to enhanced myelin regeneration. The results of the laboratory research shed light on the association of obesity with multiple sclerosis (MS) and suggest a potential strategy for improving the course of demyelinating diseases.
"This work has the ability to contribute to new therapies for people with disorders such as MS," says Isobel A. Scarisbrick, Ph.D., director of the Neuroregeneration and Neurorehabilitation Laboratory at Mayo Clinic in Rochester, Minnesota. "The study connects obesity, which is a known risk factor for developing MS, with a metabolic pathway that can be therapeutically targeted to enhance myelin regeneration."
The research focused on altered NAD+ metabolism, which has been linked to both high fat consumption and MS. Previous studies have described increased expression of CD38 — the main NAD+-depleting enzyme in the central nervous system — in mouse models of demyelination.
"Few studies have evaluated the effects of a high-fat diet on the capacity for re-myelination," says Monica R. Langley, Ph.D., a research associate in the Neuroregeneration and Neurorehabilitation Laboratory.
Regenerating myelin in preclinical models
Image shows a mouse brain stained blue for cell nuclei, green for neurons and red for myelin proteins expressed by oligodendrocytes. When CD38 is inhibited, the new myelin in red coats the green neurons and appears as yellow.
The Mayo Clinic researchers used mouse models to clarify the role of CD38 in oligodendrocyte loss related to a high-fat diet and to test whether blocking CD38 would lead to myelin regeneration. The results were published in The Journal of Neuroscience in 2021.
- CD38 expression increased in mouse spinal cords following chronic high fat consumption, after focal toxin-mediated de-myelinating injury and in reactive astrocytes within active MS lesions.
- CD38 appears to work indirectly through astrocytes to promote oligodendrocyte loss and impaired differentiation.
- CD38 inhibition normalized NAD+ levels, successfully mitigating oxidative stress and inflammatory responses as well as improving the capacity for myelin generation.
"In addition to providing new therapies for people with MS, this work can also contribute to therapies for people with more-common health challenges such as obesity," Dr. Scarisbrick says.
For more information
Neuroregeneration and Rehabilitation Laboratory: Isobel A. Scarisbrick. Mayo Clinic.
Langley MR, et al. Critical role of astrocyte NAD+ glycohydrolase in myelin injury and regeneration. The Journal of Neuroscience. 2021;41:8644.
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