Low-Dose Chidamide Treatment Displays Sex-Specific Differences in the 3xTg-AD Mouse

Area of Science:

• Neuroscience
• Pharmacology
• Genetics

Background:

• Alzheimer's disease (AD) is a complex neurodegenerative disorder with a higher prevalence in women.
• Epigenetic compounds are being investigated for AD treatment, but sex-specific effects are often overlooked.
• Histone deacetylase inhibitors represent a promising class of epigenetic drugs.

Purpose of the Study:

• To investigate the sex-specific effects of chronic, low-dose chidamide (Tucidinostat), a histone deacetylase inhibitor, in the 3xTg-AD mouse model.
• To explore how chidamide influences glucose metabolism, tau pathology, and gene expression in a sex-dependent manner.
• To highlight the importance of considering sex as a biological variable in Alzheimer's disease drug discovery.

Main Methods:

• Administration of a clinically relevant histone deacetylase inhibitor, chidamide (Tucidinostat), at chronic low doses.
• Utilized the 3xTg-AD mouse model to study Alzheimer's disease.
• Analyzed glucose tolerance, brain glucose transporter expression, total tau levels, and differential gene expression.

Main Results:

• Chidamide treatment significantly improved glucose tolerance and increased brain glucose transporter expression in male mice.
• A decrease in total tau was observed in chidamide-treated mice.
• Sex-specific gene expression patterns were observed, with males showing greater differential expression than females.
• Genes in neuroinflammatory and amyloid processing pathways were upregulated in males and downregulated in females.

Conclusions:

• Chidamide exhibits sex-specific efficacy in the 3xTg-AD mouse model.
• The findings underscore the critical need to incorporate sex as a biological variable in Alzheimer's disease research and drug development.
• Understanding sex dimorphism is crucial for the successful translation of epigenetic therapies for Alzheimer's disease.