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

Epigenetic compounds have become attractive small molecules for targeting the multifaceted aspects of Alzheimer’s disease (AD). Although AD disproportionately affects women, most of the current literature investigating epigenetic compounds for the treatment of AD do not report sex-specific results....

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Bibliographic Details
Published inBiomolecules (Basel, Switzerland) Vol. 13; no. 9; p. 1324
Main Authors Dennison, Jessica, Mendez, Armando, Szeto, Angela, Lohse, Ines, Wahlestedt, Claes, Volmar, Claude-Henry
Format Journal Article
LanguageEnglish
Published Basel MDPI AG 29.08.2023
MDPI
Subjects
3xTg-AD mouse
Age
Alzheimer's disease
Alzheimer’s
Amyloid
Animals
Antimitotic agents
Antineoplastic agents
Dosage and administration
Drug dosages
Drug therapy
Enzyme inhibitors
Epigenetics
Females
Gender differences
Gene expression
Glucose
Glucose tolerance
HDAC inhibitor
Histone deacetylase
Inflammation
Insulin
Males
Motor ability
Neurodegenerative diseases
Pharmacology, Experimental
Physiological aspects
Proteins
Sex differences
Sexual dimorphism
Software
Tau protein
Testing
United States
United States > US
Germany
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Summary:Epigenetic compounds have become attractive small molecules for targeting the multifaceted aspects of Alzheimer’s disease (AD). Although AD disproportionately affects women, most of the current literature investigating epigenetic compounds for the treatment of AD do not report sex-specific results. This is remarkable because there is rising evidence that epigenetic compounds intrinsically affect males and females differently. This manuscript explores the sexual dimorphism observed after chronic, low-dose administration of a clinically relevant histone deacetylase inhibitor, chidamide (Tucidinostat), in the 3xTg-AD mouse model. We found that chidamide treatment significantly improves glucose tolerance and increases expression of glucose transporters in the brain of males. We also report a decrease in total tau in chidamide-treated mice. Differentially expressed genes in chidamide-treated mice were much greater in males than females. Genes involved in the neuroinflammatory pathway and amyloid processing pathway were mostly upregulated in chidamide-treated males while downregulated in chidamide-treated females. This work highlights the need for drug discovery projects to consider sex as a biological variable to facilitate translation.
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ISSN:2218-273X
2218-273X
DOI:10.3390/biom13091324