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

Molecular Psychiatry volume 28, pages 4877–4888 (2023)Cite this article

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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.

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Fig. 1: Selective activation of β2-AR, not β1-AR, mimics the effects of EE in enhancing hippocampal LTP and preventing AD brain-derived Aβ oligomers from blocking it.
Fig. 2: HDAC2 but not HDAC1 is implicated in β-AR activation in response to physiologic stimuli.
Fig. 3: Activation of β-ARs decreases, while soluble Aβ oligomers increase, nuclear HDAC2 in mouse primary neurons.
Fig. 4: HDAC inhibitors prevent oAβ impairment of LTP and require activation of β2-AR.
Fig. 5: Activation of β2-AR or inhibition of HDAC protects against oAβ-mediated impairment of synaptotoxicity through an anti-inflammatory mechanism.
Fig. 6: Both a β2-AR agonist and an HDAC2 inhibitor prevent AD-brain derived oAβ-induced toxicity in human neurons.

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Acknowledgements

Supported by NIH grants P01AG015379 (DJS), and R01AG006173, the Davis Amyloid Prevention Program (DJS) and support (to SL) from the Massachusetts Alzheimer’s Disease Research Center (5P50 AG 005134). Support to DZ from Henan Key Laboratory of Neural Regeneration and Neurorestoration (HNSJXF-2021-001). We also thank Dr. Yang K Xiang (University of California Davis) for providing β2-AR knockout mice and Dr. Andrew Stern for helpful discussions.

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Authors and Affiliations

  1. Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, 02115, USA

    Ming Jin, Zhiyun Wei, Nagendran Ramalingam, Wen Liu, Dennis J. Selkoe & Shaomin Li

  2. Department of Neurology, Xinxiang Medical University, Xinxiang, 453100, China

    Meng Xiao, Anqi Xu, Xiaohan Yu, Qingyang Song, Jianhua Zhao & Dainan Zhang

  3. Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, 518172, China

    Meng Xiao

  4. Henan Key Laboratory of Neurorestoratology, Xinxiang, Henan, 453100, China

    Jianhua Zhao

  5. Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China

    Dainan Zhang

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  1. Ming Jin
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Contributions

MJ, ZW, NR, MX, and SL conducted the research, WL was responsible for preparing the human AD brain extract. AX, XY, and QS assisted in the analysis of the data. JZ and DZ supervised the collection and quality control of cytokine data. SL drafted the initial version of the paper; SL and DJS designed the research and supervised the study procedures. All authors participated in reviewing and editing the manuscript.

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Correspondence to Shaomin Li.

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DJS is a Director and provides consulting to Prothena Biosciences and has served on an advisory board for Eisai. All other authors declare no competing financial or non-financial interests.

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Jin, M., Wei, Z., Ramalingam, N. et al. Activation of β2-adrenergic receptors prevents AD-type synaptotoxicity via epigenetic mechanisms. Mol Psychiatry 28, 4877–4888 (2023). https://doi.org/10.1038/s41380-023-02145-5

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