β1-adrenergic receptor activation enhances memory in Alzheimer's disease model

OBJECTIVE: Deficits in social recognition and learning of social cues are major symptoms of neurodegenerative disorders such as Alzheimer's disease (AD). Here, we studied the role of β(1)-noradrenergic signaling in cognitive function to determine whether it could be used as a potential therapeutic target for AD. METHODS: Using pharmacological, biochemical, and behavioral tools, we assessed social recognition and the β(1)-adrenergic receptor (ADR) and its downstream protein kinase A (PKA)/phospho-cAMP response element-binding protein (pCREB) signaling cascade in the medial amygdala (MeA) in Thy1-hAPP(Lond/Swe+)(APP) mouse model of AD. RESULTS: Our results demonstrated that APP mice display a significant social recognition deficit which is dependent on the β(1)-adrenergic system. Moreover, betaxolol, a selective β(1)-ADR antagonist, impaired social but not object/odor learning in C57Bl/6 mice. Our results identifies activation of the PKA/pCREB downstream of β(1)-ADR in MeA as responsible signaling cascade for learning of social cues in MeA. Finally, we found that xamoterol, a selective β(1)-ADR partial agonist, rescued the social recognition deficit of APP mice by increasing nuclear pCREB. INTERPRETATION: Our data indicate that activation of β(1)-ADR in MeA is essential for learning of social cues, and that an impairment of this cascade in AD may contribute to pathogenesis and cognitive deficits. Therefore, selective activation of β(1)-ADR may be used as a therapeutic approach to rescue memory deficits in AD. Further safety and translational studies will be needed to ensure the safety of this approach.