Small molecule targeting long noncoding RNA GAS5 administered intranasally improves neuronal insulin signaling and decreases neuroinflammation in an aged mouse model

• Published in: Scientific reports Vol. 13; no. 1; p. 317
• Main Authors: Patel, Rekha S., Lui, Ashley, Hudson, Charles, Moss, Lauren, Sparks, Robert P., Hill, Shannon E., Shi, Yan, Cai, Jianfeng, Blair, Laura J., Bickford, Paula C., Patel, Niketa A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.01.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 631/337; 631/337/384; 692/4017; 692/700/1518; Age; Aging; Alzheimer's disease; Animals; Brain research; Cognition & reasoning; Dementia; Dementia disorders; Diabetes; Disease Models, Animal; Gene expression; Humanities and Social Sciences; Inflammation; Insulin; Insulin - metabolism; Insulin resistance; Kinases; Mice; MicroRNAs - genetics; Molecular dynamics; multidisciplinary; Neurodegeneration; Neurodegenerative diseases; Neuroinflammatory Diseases; Neurons - metabolism; Non-coding RNA; Phosphorylation; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Science; Science (multidisciplinary); Signal Transduction; Tau protein; Toll-like receptors; Transcriptomics; Veterans
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-27126-6

Shifts in normal aging set stage for neurodegeneration and dementia affecting 1 in 10 adults. The study demonstrates that lncRNA GAS5 is decreased in aged and Alzheimer’s disease brain. The role and targets of lncRNA GAS5 in the aging brain were elucidated using a GAS5-targeting small molecule NPC86, a frontier in lncRNA-targeting therapeutic. Robust techniques such as molecular dynamics simulation of NPC86 binding to GAS5, in vitro functional assays demonstrating that GAS5 regulates insulin signaling, neuronal survival, phosphorylation of tau, and neuroinflammation via toll-like receptors support the role of GAS5 in maintaining healthy neurons. The study demonstrates the safety and efficacy of intranasal NPC86 treatment in aged mice to improve cellular functions with transcriptomic analysis in response to NPC86. In summary, the study demonstrates that GAS5 contributes to pathways associated with neurodegeneration and NPC86 has tremendous therapeutic potential to prevent the advent of neurodegenerative diseases and dementias.