UVA Health researchers have discovered a molecule in the brain responsible for orchestrating immune system responses to Alzheimer’s disease and multiple sclerosis (MS), potentially allowing doctors to supercharge the body’s ability to fight these and other devastating neurological diseases.
The molecule the researchers identified, called a kinase, is crucial for both clearing the plaque buildup associated with Alzheimer’s disease and preventing the buildup of debris that causes MS, the researchers found. It does this, the researchers showed, by directing the activity of brain cleaners called microglia. These immune cells were once largely ignored by scientists but have emerged in recent years as key players in brain health.
Important new UVA findings may one day allow doctors to increase microglia activity to treat or protect patients against Alzheimer’s disease, MS and other neurodegenerative diseases, the researchers report.
Unfortunately, doctors currently do not have effective treatments to target the root causes of most neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease or ALS. [amyotrophic lateral sclerosis, commonly called Lou Gehrig’s disease]. In our studies, we discovered a master controller of cell type and processes necessary to protect the brain from these disorders. Our work further shows that targeting this novel pathway provides a powerful strategy to eliminate toxic culprits that cause memory loss and impaired motor control in neurodegenerative diseases. »
John Lukens, PhD, Sprincipal researcher, University of Virginia School of Medicine, Center for Brain Immunology and Glia (BIG), Carter Immunology Center, and UVA Brain Institute
Toxic Brain Accumulation
Many neurodegenerative diseases, including Alzheimer’s disease and multiple sclerosis, are thought to be caused by the brain’s inability to cleanse itself of toxic buildup. Recent advances in neuroscience research have shed light on the importance of microglia in clearing harmful debris from the brain, but the new UVA discovery offers practical insights into how this cleaning process occurs – and the disastrous consequences when it does not occur.
Using a mouse model of Alzheimer’s disease, UVA researchers found that a lack of the molecule they had identified, spleen tyrosine kinase, triggered plaque buildup in the brain and caused mouse memory loss – like the symptoms seen in humans with Alzheimer’s disease. Additionally, neuroscientists were able to reduce plaque buildup by activating this molecule and microglia in the brain, suggesting a potential therapeutic approach for human patients, although this would require much more research and testing.
“Our work has described a critical element of microglial function in Alzheimer’s disease and MS,” said researcher Hannah Ennerfelt, first author of a new scientific paper describing the findings. “Understanding the underlying biology of these cells during neurodegeneration may allow scientists and physicians to develop increasingly informed and effective therapeutic interventions.”
The absence of the molecule in a mouse model of MS, meanwhile, led to the buildup of damaged myelin, a protective coating on nerve cells. When myelin is damaged, cells cannot transmit messages properly, causing MS symptoms such as mobility problems and muscle spasms. UVA researchers conclude in a new scientific paper that the molecule they identified, abbreviated as SYK, is “critically involved” in the crucial removal of myelin debris.
“If stimulation of SYK activity in microglia can reduce the amount of myelin debris in MS lesions, developing new drugs to target SYK could halt the progression of MS and help reverse the damage,” said said Elizabeth L. Frost, PhD, critical researcher on the project. “This is a particularly promising option given that most drugs currently available for MS treatment attenuate adaptive immunity. These immunosuppressive drugs lead to susceptibility to infections and a higher risk of potentially such as progressive multifocal leukoencephalopathy. Additionally, some forms of MS do not have a strong involvement of the immune system, and therefore there are currently very limited treatment options for these patients.”
“Targeting SYK in microglia,” she noted, “would circumvent multiple limitations of current MS treatments.”
Based on their promising results, the researchers report that targeting the molecule to boost immune activity in the brain could offer a way to treat not just Alzheimer’s disease and MS, but also a ‘range’ of diseases. neurodegenerative.
“These findings are particularly exciting because they point to a processing pathway where we could alter the behavior of these native brain cells, microglia, to behave in a more neuroprotective way,” said researcher Coco Holliday, a student. UVA undergraduate working in the Lukens lab. . “It could potentially be applied to a variety of different neurological diseases that all share the problem of a buildup of toxic waste in the brain. It was a very exciting project to be involved in.”
The researchers published their findings in the scientific journal Cell. The team consisted of Ennerfelt, Frost, Daniel A. Shapiro, Holliday, Kristine E. Zengeler, Gabrielle Voithofer, Ashley C. Bolte, Catherine R. Lammert, Joshua A. Kulas, Tyler K. Ulland, and Lukens. The researchers have reported no financial interest in the work.
The research was funded by the National Institute of Aging of the National Institutes of Health, grantRF1AG071996-01; the National Institute of Neurological Disorders and Stroke, grant R01NS106383; the Alzheimer’s Association, grant ADSF-21-816651; the Cure Alzheimer Fund; The Owens Family Foundation; and several training scholarships.
Ennerfelt, H., et al. (2022) SYK coordinates neuroprotective microglial responses in neurodegenerative diseases. Cell. doi.org/10.1016/j.cell.2022.09.030.