Activation of β₂-adrenergic receptor promotes dendrite ramification and spine generation in APP/PS1 mice

Alzheimer's disease (AD) is the most common neurodegenerative disorder, and currently there is no effective cure for this devastating disease. Decreases in the levels of β₂-adrenoceptor (β₂-AR) and norepinephrine have been reported in several regions of AD brains. The activation of β₂AR can prevent the amyloid β (Aβ)-mediated inhibition of LTP (Long-term potentiation), but the mechanism is not fully understood. Here, we used APP/PS1 mice to study whether the activation of β₂AR could remodel synaptic and/or dendritic plasticity. We found that the activation of β₂AR by Clenbuterol (Clen) ameliorated memory deficits and promoted dendrite ramification and spine generation in hippocampal CA1 neurons, which was accompanied by the upregulation of postsynaptic density protein 95 (PSD95), synapsin 1 and synaptophysin. Conversely, the inhibition of β₂AR by a siRNA blocked the Clen-induced increase in dendrite ramification and dendritic spines in primary hippocampal neurons. Furthermore, the activation of β₂AR decreased cerebral amyloid plaques through the up-regulation of α-secretase activity and by decreasing the phosphorylation of APP at Thr668. Based on the roles of β₂AR in dendrite ramification and spine generation, memory deficits and AD pathogenesis, compounds designed to activate β₂AR might shed light on the cure of AD.