Work

Low-dose dietary vorinostat increases brain histone acetylation levels and reduces oxidative stress in an Alzheimer's disease mouse model

Year: 2025

Type: article

Abstract: Background Alzheimer's disease (AD) disrupts histone acetylation/deacetylation homeostasis, blocking access of transcription factors to DNA, and compromising learning. Vorinostat (VOR), the only FDA-approved HDAC inhibitor that is orally bioavailable and brain penetrant, confers neuroprotection in AD models. We delivered VOR via diet in an AD mouse model, examining tolerability, accompanied by biochemical analyses. Objective Our objective was to examine dietary delivery of vorinostat for tolerability, including changes to histone acetylation, amyloid-β (Aβ) production, oxidative stress (OS), mitochondrial health, and synaptic integrity. Methods Food pellets containing control, 0.18 mg/g (low-dose) and 0.36 mg/g (high-dose) VOR were administered to hAβ-KI AD mice for 14 days. Brain acetyl-histone H3 (AH3), total H3 expression, and synaptic markers were measured via Western blot. Aβ, H 2 O 2 , antioxidant capacity, lipid peroxidation (via 4-hydroxynonenal (4-HNE)), adenosine triphosphate (ATP), and citrate synthase (CS) activity were measured in brain tissue. Results VOR inhibited brain HDAC enzyme activity and increased AH3 and H3 expression at both VOR doses. Aβ and synaptic proteins were not significantly affected; however, OS markers were improved at both doses. Both doses increased CS activity, while ATP was increased only at the low dose. Finally, low-dose VOR was tolerable over 2 months. Conclusions We established that low-dose VOR, delivered via diet, is tolerable in AD mice, successfully inhibiting brain HDAC activity while reducing OS and improving mitochondrial health. This study improves existing preclinical experimental designs by enabling noninvasive manipulation of histone acetylation through dietary intervention. This route of administration provides advantages for future preclinical animal studies.

Source: Journal of Alzheimer s Disease

DOI: 10.1177/13872877251352107