summary: A new discovery has revealed that ponsimode, a drug originally used to treat multiple sclerosis, shows potential in treating Alzheimer’s disease. The researchers found that the drug reduces nerve inflammation, which is a critical factor in the development of Alzheimer’s disease.
Bonsimode has already been approved by the US Food and Drug Administration for the treatment of MS, and it can be immediately reintroduced to treat Alzheimer’s disease. Experiments on mouse models and human brain samples support the study.
- Bonisemod, an FDA-approved drug for multiple sclerosis, has been shown to be effective in reducing one of the hallmarks of Alzheimer’s disease: neuroinflammation.
- The researchers focused on microglia, which are integral to regulating inflammatory responses in the brain, and found that punsimod reprograms them to remove toxic proteins.
- The study, which included tests on mice and human brain samples, indicates that punisemod not only reduces neuroinflammation, but also improves memory.
source: University of Kentucky
A team of researchers at the University of Kentucky has discovered that a drug used to treat multiple sclerosis (MS) may be effective as a treatment for Alzheimer’s disease.
Alzheimer’s disease is a progressive and incurable neurological disorder. It is estimated that 6.2 million Americans age 65 or older live with the disease, which affects cognitive function, memory, and behavior.
“We stand on the threshold of a critical quest to develop new therapeutic strategies against Alzheimer’s disease,” said Erhard Biebrich, PhD, professor in the Department of Physiology at the UK Medical School.
“We’ve discovered that a drug already on the market, ponesimod (brand name ‘Ponvory’), can reduce one of the hallmarks of this disease: neuroinflammation.”
The results were published in the journal Biomedicinepart of The Lancet Discovery Science series in August.
The team studied Bonisimod, an oral drug approved by the US Food and Drug Administration (FDA) to treat relapsing forms of MS.
The drug 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 called sphingosine-1-phosphate, the function of which has been studied in Biebrich’s lab.
“We are the first to show the efficacy of punisemod in a mouse model for the treatment of Alzheimer’s disease,” Biebrich said. “Because this drug is already in clinical use for the treatment of relapsing-remitting multiple sclerosis, it is immediately available for use in Alzheimer’s disease as well.”
British researchers focused on a specific type of cell found in the central nervous system called microglia. Cells have many functions in our bodies, including regulating inflammatory responses in the central nervous system, the brain and spinal cord.
Dysfunctional microglia are linked to neurodegenerative diseases such as Alzheimer’s disease because these cells help clear the buildup of abnormal protein deposits in the brain, which is a hallmark of the disease. These build-ups disrupt communication between neurons in the brain and eventually they die.
“Removing these proteins is an important goal for treating Alzheimer’s disease,” said Zihui Zhou, PhD, first author of the study and one of the scientists in Biebrich’s lab.
“In our study, we reprogrammed microglia into neuronal protective cells that clean up toxic proteins in the brain, reduce the neuroinflammatory pathology of Alzheimer’s disease, and improve memory in a mouse model.”
As part of the project, the researchers studied mice with specific genetic strains that express key features of Alzheimer’s disease in their brains. They treated half of the mice with poncemod and measured the activity of specific brain cells. The spatial memory of the mice was also tested through the maze behavior test.
“This specific test is a measure of the rats’ automatic tendency to switch their free options to enter both arms of the maze,” Zhou said. “Our tests indicate that punisemod rescues attention and working memory in mice with advanced Alzheimer’s disease.”
The scientists also worked with Alzheimer’s Research UK within the Sanders Brown Center on Aging to obtain samples of the human brain to study. The data gathered from those tests was consistent and indicated that ponisemod could be used as a treatment for Alzheimer’s disease.
“Neural inflammation is a hallmark of Alzheimer’s disease, a major cause of disease progression and a promising target for treatment,” Biebrich said.
“Our study shows strong experimental evidence that punisemod may be a therapeutic drug that not only reduces neuroinflammation, but also promotes clearance of neurotoxic proteins in the brain in middle- and late-stage Alzheimer’s disease.”
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“S1P receptor 1 antagonist Ponesimod reduces TLR4-induced neuroinflammation and increases Aβ clearance in 5XFAD mice.Written by Zhou Zhou et al. iBiomedicine
S1P receptor 1 antagonist Ponesimod reduces TLR4-induced neuroinflammation and increases Aβ clearance in 5XFAD mice.
Previously, we showed that spinster sphingosine-1-phosphate (S1P) transporter 2 (Spns2) mediates the activation of microglia in response to amyloid-β (Aβ) peptide. Here, we investigated whether Ponesimod, a functional antagonist of S1P receptor 1 (S1PR1), prevents Aβ-induced glial cell activation and Alzheimer’s disease (AD) pathogenesis.
We used primary cultures of glial cells and a 5XFAD mouse model to determine the effect of Aβ and Ponesimod on glial activation, Aβ phagocytosis, levels of cytokines and pro-inflammatory signaling pathways, AD pathology, and cognitive performance.
aβ42 Increased levels of TLR4 and S1PR1, resulting in their complex formation. Ponesimod inhibits the increase in the levels of TLR4 and S1PR1, as well as their complex formation. It also decreased 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, ponsimode reduced levels of TNF-α and CXCL10, which activate TLR4 and Stat1. It also increases the level of IL-33, an anti-inflammatory cytokine that promotes Aβ42 phagocytosis by microglia. As a result of these changes, bonsimode 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 the Y maze test.
Ponesimod targeting of S1PR1 is a promising therapeutic approach to reprogram microglia, reduce neuroinflammation, and increase Aβ clearance in Alzheimer’s disease.
NIH R01AG064234, RF1AG078338, R21AG078601, VA I01BX003643.