Basic Science and Pathogenesis

In Alzheimer's disease (AD), histone acetylation is disrupted, suggesting loss of transcriptional control. Moreover, converging evidence suggests an age- and AD-dependent loss of transcription controlled by all-trans-retinoic acid (ATRA), the bioactive metabolite of vitamin A (VA). Antioxidant depletion causes oxidative stress (OS). Nrf2-mediated antioxidant defenses are triggered by OS. Here, we investigated roles of VA, histone acetylation, Nrf2, and OS in vitro. Finally, we established a dietary dose of vorinostat that crosses the blood brain barrier and promotes histone acetylation in AD mouse brain. For in vitro studies, mouse HT22 cells were treated with vorinostat (up to 40 µM), ATRA, and/or H O . MTT and lipid peroxidation assays were performed. Acetylated histone H3 and Nrf2 expression were examined via western blot (WB) and immunocytochemistry (ICC). For in vivo studies, the hAb-KI AD mice were treated with 0.18 or 0.36 mg vorinostat/gram of diet (125 or 250 mg/kg/week for 2 weeks). HDAC activity in brain tissue was examined via histone H3 acetylation and enzyme activity via WB and colorimetric ELISA. Vorinostat and ATRA treatment (up to 20 μM) had no significant cytotoxic effects on HT22 cells. H O alone (25-50 µM) caused ∼30-40% cell death (p