Coutellier Laurence, Ardestani Pooneh Memar, Shamloo Mehrdad
Behavioral and Functional Neuroscience Laboratory, Stanford University School of Medicine, Stanford, CA, USA.
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA ; Behavioral and Functional Neuroscience Laboratory, Stanford University School of Medicine, Stanford, CA, USA.
Ann Clin Transl Neurol. 2014 May 1;1(5):348-360. doi: 10.1002/acn3.57.
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-noradrenergic signaling in cognitive function to determine whether it could be used as a potential therapeutic target for AD.
Using pharmacological, biochemical and behavioral tools, we assessed social recognition and the β-adrenergic receptor (ADR) and its downstream PKA/phospho-CREB (pCREB) signaling cascade in the medial amygdala (MeA) in Thy1-hAPP(APP) mouse model of AD.
Our results demonstrated that APP mice display a significant social recognition deficit which is dependent on the β-adrenergic system. Moreover, betaxolol, a selective β-ADR antagonist, impaired social but not object/odor learning in C57Bl/6 mice. Our results identifies activation of the PKA/pCREB downstream of β-ADR in MeA as responsible signaling cascade for learning of social cues in MeA. Finally, we found that xamoterol, a selective β-ADR partial agonist, rescued the social recognition deficit of APP mice by increasing nuclear pCREB.
Our data indicate that activation of β-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-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.
社交认知缺陷以及对社交线索的学习障碍是神经退行性疾病（如阿尔茨海默病，AD）的主要症状。在此，我们研究了β-去甲肾上腺素能信号在认知功能中的作用，以确定其是否可作为AD的潜在治疗靶点。
我们使用药理学、生物化学和行为学方法，评估了AD的Thy1-hAPP（APP）小鼠模型中内侧杏仁核（MeA）的社交认知、β-肾上腺素能受体（ADR）及其下游的PKA/磷酸化-CREB（pCREB）信号级联反应。
我们的结果表明，APP小鼠存在明显的社交认知缺陷，且该缺陷依赖于β-肾上腺素能系统。此外，选择性β-ADR拮抗剂倍他洛尔损害了C57Bl/6小鼠的社交学习，但未影响其物体/气味学习。我们的结果确定了MeA中β-ADR下游的PKA/pCREB激活是MeA中社交线索学习的负责信号级联反应。最后，我们发现选择性β-ADR部分激动剂扎莫特罗通过增加核pCREB挽救了APP小鼠的社交认知缺陷。
我们的数据表明，MeA中β-ADR的激活对于社交线索的学习至关重要，而AD中该信号级联反应的受损可能导致发病机制和认知缺陷。因此，选择性激活β-ADR可作为挽救AD记忆缺陷的治疗方法。需要进一步的安全性和转化研究来确保该方法的安全性。
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