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

Abstract

BackgroundAlzheimer'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.ObjectiveOur 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.MethodsFood 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, H₂O₂, antioxidant capacity, lipid peroxidation (via 4-hydroxynonenal (4-HNE)), adenosine triphosphate (ATP), and citrate synthase (CS) activity were measured in brain tissue.ResultsVOR 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.ConclusionsWe 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.