Dual TYK2/JAK1 kinase inhibitor suppresses cytoplasmic dsRNA-induced toxic innate immune response in neurodegenerative mice
OA Version
Citation
Abstract
Neurodegenerative diseases such as Alzheimer’s disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) affect millions of people worldwide. Although there are no cures for these debilitating diseases, new potential treatment plans to help patients are being developed. Recent studies have shown that neuroinflammation is a cause of neurodegeneration, and it is triggered by the presence of cytoplasmic double-stranded RNA (cdsRNA) in the cytoplasm of neurons. This insight is being leveraged translationally to produce drugs that block the type I interferon signaling pathway, the innate immune response triggered by cdsRNA, and neural cell death. In this study we examined whether two compounds, TLL041 and TLL082, which inhibit the activity of TYK2 and JAK1 kinases associated with signaling the type I interferon receptor, can block neuroinflammation and cell death. The effects of TLL041 and TLL082 were evaluated in vivo in the Nd1 mouse model of neurodegeneration, compared to the isogenic wildtype BL6 mouse. Two doses of each drug (3.3 mg/kg and 10 mg/kg) were administered for 28 consecutive days via oral gavage and the inflammatory marker expression levels in the olfactory sensory neurons determined by qPCR and IHC antibody staining. Analysis demonstrated that neuroinflammation in Nd1 mice was significantly reduced (p < 0.05). These findings indicate that TYK2 and JAK1 kinases are effective drug targets for neuroinflammation in this model of neurodegenerative disease and may potentially be used to slow the progression of neurodegenerative diseases.
Description
2024