Summary: A groundbreaking revealed that ponesimod, a drug originally used to treat multiple sclerosis, shows potential in treating Alzheimer’s disease. Researchers found that the medication reduces neuroinflammation, a critical factor in Alzheimer’s progression.
Already approved by the FDA for treating MS, ponesimod could immediately be repurposed for Alzheimer’s treatment. Experiments in mouse models and human brain samples back the study.
Key Facts:
- Ponesimod, an FDA-approved medication for multiple sclerosis, was found effective in reducing one of the hallmarks of Alzheimer’s disease: neuroinflammation.
- Researchers focused on microglia cells, which are integral in regulating inflammatory responses in the brain, and found that ponesimod reprograms them to clear toxic proteins.
- The study, which included tests in mice and human brain samples, indicates that ponesimod not only mitigates neuroinflammation but also improves memory.
Source: University of Kentucky
A team of researchers at the University of Kentucky has found that a drug used to treat multiple sclerosis (MS) is potentially effective as a therapy for Alzheimer’s disease.
Alzheimer’s is a progressive and irreversible neurological disorder. It’s estimated 6.2 million Americans aged 65 and older are living with the disease that affects cognitive function, memory and behavior.
“We stand at the threshold of a critical endeavor to develop new treatment strategies against Alzheimer’s disease,” said Erhard Bieberich, Ph.D., a professor in the Department of Physiology in the UK College of Medicine.
“We’ve uncovered that a medication already on the market, ponesimod (brand name ‘Ponvory’), can reduce one of the hallmarks of this disease: neuroinflammation.”
The findings were published in the journal eBioMedicine, part of The Lancet Discovery Science series in August.
The team studied ponesimod, an oral medication that the U.S. Food and Drug Administration (FDA) has approved to treat relapsing forms of MS.
The medication reduces inflammation in the brain by targeting a specific receptor in the immune system to help regulate the body’s response and prevent it from attacking the central nervous system. This receptor is activated by a lipid termed sphingosine-1-phosphate, the function of which is studied by the Bieberich lab.
“We are the first to show that ponesimod is effective in a mouse model for Alzheimer’s disease,” said Bieberich. “Since this drug is already in clinical use for therapy of relapsing multiple sclerosis, it is immediately available to be used in Alzheimer’s disease therapy as well.”
UK researchers homed in on a specific type of cell found in the central nervous system called microglia. The cells have several functions in our bodies, including regulating inflammatory responses in the central nervous system—the brain and the spinal cord.
Dysfunctional microglia are connected to neurodegenerative diseases like Alzheimer’s because those cells help clear out the buildup of abnormal protein deposits in the brain—a distinct characteristic of the disease. Those buildups disrupt the communication between the brain’s nerve cells and eventually die off.
“The clearance of those proteins is an important target for Alzheimer’s disease therapy,” said Zhihui Zhu, Ph.D., first-author of the study and one of the scientists in Bieberich’s lab.
“In our study, we reprogrammed microglia into neuron-protective cells that clean up toxic proteins in the brain, reduce Alzheimer’s neuroinflammatory pathology, and improve memory in the mouse model.”
As part of the project, researchers studied mice with specific genetic strains that express the major features of Alzheimer’s in their brains. They treated half of the mice with ponesimod and measured specific cell activity in the brain. The mice’s spatial memory was also tested through a maze behavior test.
“That specific test is a measure of the spontaneous tendency of the mice to alternate their free choices to enter the two arms of the maze,” said Zhu. “Our tests indicate ponesimod rescues attention and working memory in mice with advanced Alzheimer’s pathology.”
Scientists also worked with UK’s Alzheimer’s Disease Research Center within the Sanders-Brown Center on Aging to obtain human brain samples to study. The data collected from those tests were consistent and also indicated ponesimod can be used as a therapy for Alzheimer’s.
“Neuroinflammation is a hallmark of Alzheimer’s, one of the major causes for disease progression and a promising target for therapy,” said Bieberich.
“Our study shows strong experimental evidence that ponesimod may be a therapeutic drug, which not only reduces neuroinflammation but also enhances the clearance of neurotoxic proteins in the brain in middle and late-stage Alzheimer’s.”
About this Alzheimer’s disease and neuropharmacology research news
Author: Lindsay Travis
Source: University of Kentucky
Contact: Lindsay Travis – University of Kentucky
Image: The image is credited to Neuroscience News
Original Research: Open access.
“The S1P receptor 1 antagonist Ponesimod reduces TLR4-induced neuroinflammation and increases Aβ clearance in 5XFAD mice” by Zhihui Zhu et al. EBioMedicine
Abstract
The S1P receptor 1 antagonist Ponesimod reduces TLR4-induced neuroinflammation and increases Aβ clearance in 5XFAD mice
Background
Previously, we showed that the sphingosine-1-phosphate (S1P) transporter spinster 2 (Spns2) mediates activation of microglia in response to amyloid β peptide (Aβ). Here, we investigated if Ponesimod, a functional S1P receptor 1 (S1PR1) antagonist, prevents Aβ-induced activation of glial cells and Alzheimer’s disease (AD) pathology.
Methods
We used primary cultures of glial cells and the 5XFAD mouse model to determine the effect of Aβ and Ponesimod on glial activation, Aβ phagocytosis, cytokine levels and pro-inflammatory signaling pathways, AD pathology, and cognitive performance.
Findings
Aβ42 increased the levels of TLR4 and S1PR1, leading to their complex formation. Ponesimod prevented the increase in TLR4 and S1PR1 levels, as well as the formation of their complex. It also reduced the activation of the pro-inflammatory Stat1 and p38 MAPK signaling pathways, while activating the anti-inflammatory Stat6 pathway. This was consistent with increased phagocytosis of Aβ42 in primary cultured microglia. In 5XFAD mice, Ponesimod decreased the levels of TNF-α and CXCL10, which activate TLR4 and Stat1. It also increased the level of IL-33, an anti-inflammatory cytokine that promotes Aβ42 phagocytosis by microglia. As a result of these changes, Ponesimod decreased the number of Iba-1+ microglia and GFAP+ astrocytes, and the size and number of amyloid plaques, while improving spatial memory as measured in a Y-maze test.
Interpretation
Ponesimod targeting S1PR1 is a promising therapeutic approach to reprogram microglia, reduce neuroinflammation, and increase Aβ clearance in AD.
Funding
NIH R01AG064234, RF1AG078338, R21AG078601, VA I01BX003643.
