Abstract

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.

Details

Title
Small molecule targeting long noncoding RNA GAS5 administered intranasally improves neuronal insulin signaling and decreases neuroinflammation in an aged mouse model
Author
Patel, Rekha S. 1 ; Lui, Ashley 2 ; Hudson, Charles 1 ; Moss, Lauren 3 ; Sparks, Robert P. 4 ; Hill, Shannon E. 5 ; Shi, Yan 6 ; Cai, Jianfeng 6 ; Blair, Laura J. 7 ; Bickford, Paula C. 8 ; Patel, Niketa A. 9 

 James A. Haley Veterans Hospital, Research Service, Tampa, USA (GRID:grid.281075.9) (ISNI:0000 0001 0624 9286) 
 University of South Florida, Department of Molecular Medicine, Tampa, USA (GRID:grid.170693.a) (ISNI:0000 0001 2353 285X) 
 University of South Florida, Department of Neurosurgery and Brain Repair, Tampa, USA (GRID:grid.170693.a) (ISNI:0000 0001 2353 285X) 
 UMass Chan Medical School, Worcester, USA (GRID:grid.170693.a) 
 University of South Florida, Department of Molecular Medicine, Tampa, USA (GRID:grid.170693.a) (ISNI:0000 0001 2353 285X); University of South Florida, USF Health Byrd Institute, Tampa, USA (GRID:grid.170693.a) (ISNI:0000 0001 2353 285X) 
 University of South Florida, Department of Chemistry, Tampa, USA (GRID:grid.170693.a) (ISNI:0000 0001 2353 285X) 
 James A. Haley Veterans Hospital, Research Service, Tampa, USA (GRID:grid.281075.9) (ISNI:0000 0001 0624 9286); University of South Florida, Department of Molecular Medicine, Tampa, USA (GRID:grid.170693.a) (ISNI:0000 0001 2353 285X); University of South Florida, USF Health Byrd Institute, Tampa, USA (GRID:grid.170693.a) (ISNI:0000 0001 2353 285X) 
 James A. Haley Veterans Hospital, Research Service, Tampa, USA (GRID:grid.281075.9) (ISNI:0000 0001 0624 9286); University of South Florida, Department of Neurosurgery and Brain Repair, Tampa, USA (GRID:grid.170693.a) (ISNI:0000 0001 2353 285X) 
 James A. Haley Veterans Hospital, Research Service, Tampa, USA (GRID:grid.281075.9) (ISNI:0000 0001 0624 9286); University of South Florida, Department of Molecular Medicine, Tampa, USA (GRID:grid.170693.a) (ISNI:0000 0001 2353 285X) 
Pages
317
Publication year
2023
Publication date
2023
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2761462029
Copyright
© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.