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

Authors

  • Laurence Coutellier,

    1. Behavioral and Functional Neuroscience Laboratory, Stanford University School of Medicine, Stanford, California
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    • These authors contributed equally to this work.
  • Pooneh Memar Ardestani,

    1. Behavioral and Functional Neuroscience Laboratory, Stanford University School of Medicine, Stanford, California
    2. Department of Neurosurgery, Stanford University School of Medicine, Stanford, California
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    • These authors contributed equally to this work.
  • Mehrdad Shamloo

    Corresponding author
    1. Behavioral and Functional Neuroscience Laboratory, Stanford University School of Medicine, Stanford, California
    2. Department of Neurosurgery, Stanford University School of Medicine, Stanford, California
    • Correspondence

      Mehrdad Shamloo, 1050 Arastradero Road, Bld A”, M/C: 5589, Palo Alto, CA 94304. Tel: 6507253152; Fax: 6507257813; E-mail: mshamloo@stanford.edu

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Abstract

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 β1-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 β1-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-hAPPLond/Swe+(APP) mouse model of AD.

Results

Our results demonstrated that APP mice display a significant social recognition deficit which is dependent on the β1-adrenergic system. Moreover, betaxolol, a selective β1-ADR antagonist, impaired social but not object/odor learning in C57Bl/6 mice. Our results identifies activation of the PKA/pCREB downstream of β1-ADR in MeA as responsible signaling cascade for learning of social cues in MeA. Finally, we found that xamoterol, a selective β1-ADR partial agonist, rescued the social recognition deficit of APP mice by increasing nuclear pCREB.

Interpretation

Our data indicate that activation of β1-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 β1-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.

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