Dysregulation of histone acetylation in the APP/PS1 mouse model of Alzheimer's disease

Abstract

Epigenetic mechanisms such as post-translational histone modifications are increasingly recognized for their contribution to gene activation and silencing in the brain. Histone acetylation in particular has been shown to be important both in hippocampal long-term potentiation (LTP) and memory formation in mice. The involvement of the epigenetic modulation of memory formation has also been proposed in neuropathological models, although up to now no clear-cut connection has been demonstrated between histone modifications and the etiology of Alzheimer's disease (AD). Thus, we have undertaken preclinical studies in the APP/PS1 mouse model of AD to determine whether there are differences in histone acetylation levels during associative memory formation. After fear conditioning training, levels of hippocampal acetylated histone 4 (H4) in APP/PS1 mice were about 50% lower than in wild-type littermates. Interestingly, acute treatment with a histone deacetylase inhibitor, Trichostatin A (TSA), prior to training rescued both acetylated H4 levels and contextual freezing performance to wild-type values. Moreover, TSA rescued CA3-CA1 LTP in slices from APP/PS1 mice. Based on this evidence, we propose the hypothesis that epigenetic mechanisms are involved in the altered synaptic function and memory associated with AD. In this respect, histone deacetylase inhibitors represent a new therapeutic target to effectively counteract disease progression.

Fig. 1.

Histone acetylation reduction in APP/PS1 mice. (A) Western blotting of protein extracts from APP/PS1 and WT mice, which were injected with vehicle and TSA 2 hours before training, and euthanized 1 hour after contextual fear conditioning. Vehicle-treated APP/PS1 animals showed a decrease in acetylated H4 levels. However, TSA-treated APP/PS1 mice showed an enhancement of H4 acetylation, reaching the same levels of acetylation as TSA-treated WT mice. Results were normalized against vehicle-treated WT mice. (B) Basal acetylation levels of H4 in APP/PS1 mice and WT littermates, which were exposed to the context without receiving an electrical shock, were similar. The data shown in (A) and (B) are presented as a ratio of acetylated-H4 to total H4.

Fig. 2.

TSA injection improves contextual fear conditioning performance in APP/PS1 mice. 3 to 4 month-old APP/PS1 and WT littermates treated with TSA or vehicle 2 hours prior to training show no difference in immediate freezing in the training chamber. However, vehicle-treated APP/PS1 mice show reduced freezing responses compared to vehicle-treated littermates when tested for contextual fear conditioning 24 hours after training. Injection of TSA two hours prior to training ameliorates the deficit in freezing responses in APP/PS1 mice after 24 hours but does not further improve freezing in WT mice.

Fig. 3.

TSA reverses CA1-LTP impairment in slices from APP/PS1 mice. (A) Summary graph showing that 30 min perfusion with TSA abrogates LTP impairment in 3–4 month old APP/PS1 mice without affecting the baseline transmission. (B) Summary graph showing that 30 min perfusion with TSA does not affect LTP and baseline transmission in WT mice. These experiments were interleaved with those of APP/PS1 mice. The horizontal bar represents TSA application. The three arrows correspond to the theta-burst stimulation.