Activation of β2-adrenergic receptors prevents AD-type synaptotoxicity via epigenetic mechanisms

Abstract

We previously reported that prolonged exposure to an enriched environment (EE) enhances hippocampal synaptic plasticity, with one of the significant mechanistic pathways being activation of β₂-adrenergic receptor (β₂-AR) signaling, thereby mitigating the synaptotoxic effects of soluble oligomers of amyloid β-protein (oAβ). However, the detailed mechanism remained elusive. In this work, we recorded field excitatory postsynaptic potentials (fEPSP) in the CA1 region of mouse hippocampal slices treated with or without toxic Aβ-species. We found that pharmacological activation of β₂-AR, but not β₁-AR, selectively mimicked the effects of EE in enhancing LTP and preventing oAβ-induced synaptic dysfunction. Mechanistic analyses showed that certain histone deacetylase (HDAC) inhibitors mimicked the benefits of EE, but this was not seen in β₂-AR knockout mice, suggesting that activating β₂-AR prevents oAβ-mediated synaptic dysfunction via changes in histone acetylation. EE or activation of β-ARs each decreased HDAC2, whereas Aβ oligomers increased HDAC2 levels in the hippocampus. Further, oAβ-induced inflammatory effects and neurite degeneration were prevented by either β₂-AR agonists or certain specific HDAC inhibitors. These preclinical results suggest that activation of β₂-AR is a novel potential therapeutic strategy to mitigate oAβ-mediated features of AD.