A promising drug repurposing approach for Alzheimer's treatment: Givinostat improves cognitive behavior and pathological features in APP/PS1 mice
Qi-Chao Gao,
Ge-Liang Liu,
Qi Wang,
Sheng-Xiao Zhang,
Zhi-Lin Ji,
Zhao-Jun Wang,
Mei-Na Wu,
Qi Yu,
Pei-Feng He
Affiliations
Qi-Chao Gao
School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, Shanxi, China; Key Laboratory of Big Data for Clinical Decision Research in Shanxi Province, Taiyuan, China; Department of Physiology, Shanxi Medical University, Key Laboratory of Cellular Physiology, Ministry of Education, Key Laboratory of Cellular Physiology in Shanxi Province, Taiyuan, China
Ge-Liang Liu
School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, Shanxi, China; Key Laboratory of Big Data for Clinical Decision Research in Shanxi Province, Taiyuan, China
Qi Wang
School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, Shanxi, China; Key Laboratory of Big Data for Clinical Decision Research in Shanxi Province, Taiyuan, China
Sheng-Xiao Zhang
Department of Rheumatology and Immunology, The Second Hospital of Shanxi Medical University, Taiyuan, China; Department of Physiology, Shanxi Medical University, Key Laboratory of Cellular Physiology, Ministry of Education, Key Laboratory of Cellular Physiology in Shanxi Province, Taiyuan, China
Zhi-Lin Ji
School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, Shanxi, China; School of Public Health, Shanxi Medical University, Taiyuan, Shanxi, China
Zhao-Jun Wang
School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, Shanxi, China; Department of Physiology, Shanxi Medical University, Key Laboratory of Cellular Physiology, Ministry of Education, Key Laboratory of Cellular Physiology in Shanxi Province, Taiyuan, China
Mei-Na Wu
School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, Shanxi, China; Department of Physiology, Shanxi Medical University, Key Laboratory of Cellular Physiology, Ministry of Education, Key Laboratory of Cellular Physiology in Shanxi Province, Taiyuan, China
Qi Yu
Key Laboratory of Big Data for Clinical Decision Research in Shanxi Province, Taiyuan, China; School of Management, Shanxi Medical University, Taiyuan, China; Corresponding author. School of Management, Shanxi Medical University, Shanxi 030001, China.
Pei-Feng He
Key Laboratory of Big Data for Clinical Decision Research in Shanxi Province, Taiyuan, China; School of Management, Shanxi Medical University, Taiyuan, China; Corresponding author. School of Management, Shanxi Medical University, Shanxi 030001. China.
Alzheimer's disease (AD) is the most common neurodegenerative disease, characterized by memory loss, speech and motor defects, personality changes, and psychological disorders. The exact cause of AD remains unclear. Current treatments focus on maintaining neurotransmitter levels or targeting β-amyloid (Aβ) protein, but these only alleviate symptoms and do not reverse the disease. Developing new drugs is time-consuming, costly, and has a high failure rate. Utilizing multi-omics for drug repositioning has emerged as a new strategy. Based on transcriptomic perturbation data of over 40,000 drugs in human cells from the LINCS-L1000 database, our study employed the Jaccard index and hypergeometric distribution test for reverse transcriptional feature matching analysis, identifying Givinostat as a potential treatment for AD. Our research found that Givinostat improved cognitive behavior and brain pathology in models and enhanced hippocampal synaptic plasticity. Transcriptome sequencing revealed increased expression of mitochondrial respiratory chain complex proteins in the brains of APP/PS1 mice after Givinostat treatment. Functionally, Givinostat restored mitochondrial membrane potential, reduced reactive oxygen species, and increased ATP content in Aβ-induced HT22 cells. Additionally, it improved mitochondrial morphology and quantity in the hippocampus of APP/PS1 mice and enhanced brain glucose metabolic activity. These effects are linked to Givinostat promoting mitochondrial biogenesis and improving mitochondrial function. In summary, Givinostat offers a promising new strategy for AD treatment by targeting mitochondrial dysfunction.
