Activation of ß2-adrenergic receptors prevents AD-type synaptotoxicity via epigenetic mechanisms.
Mol Psychiatry
; 28(11): 4877-4888, 2023 Nov.
Article
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| MEDLINE
| ID: mdl-37365243
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 ß2-adrenergic receptor (ß2-AR) signaling, thereby mitigating the synaptotoxic effects of soluble oligomers of amyloid ß-protein (oAß). 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 Aß-species. We found that pharmacological activation of ß2-AR, but not ß1-AR, selectively mimicked the effects of EE in enhancing LTP and preventing oAß-induced synaptic dysfunction. Mechanistic analyses showed that certain histone deacetylase (HDAC) inhibitors mimicked the benefits of EE, but this was not seen in ß2-AR knockout mice, suggesting that activating ß2-AR prevents oAß-mediated synaptic dysfunction via changes in histone acetylation. EE or activation of ß-ARs each decreased HDAC2, whereas Aß oligomers increased HDAC2 levels in the hippocampus. Further, oAß-induced inflammatory effects and neurite degeneration were prevented by either ß2-AR agonists or certain specific HDAC inhibitors. These preclinical results suggest that activation of ß2-AR is a novel potential therapeutic strategy to mitigate oAß-mediated features of AD.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Péptidos beta-Amiloides
/
Hipocampo
Límite:
Animals
Idioma:
En
Revista:
Mol Psychiatry
Asunto de la revista:
BIOLOGIA MOLECULAR
/
PSIQUIATRIA
Año:
2023
Tipo del documento:
Article
País de afiliación:
Estados Unidos