Early synaptic deficits in the APP/PS1 mouse model of Alzheimer's disease involve neuronal adenosine A2A receptors.
Early synaptic deficits in the APP/PS1 mouse model of Alzheimer's disease involve neuronal adenosine A2A receptors.
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DOI：
10.1038/ncomms11915
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发表时间：
2016-06-17
影响因子：
16.6
通讯作者：
Mulle C
中科院分区：
文献类型：
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作者：
Viana da Silva S;Haberl MG;Zhang P;Bethge P;Lemos C;Gonçalves N;Gorlewicz A;Malezieux M;Gonçalves FQ;Grosjean N;Blanchet C;Frick A;Nägerl UV;Cunha RA;Mulle C
海马CA 3区锥体细胞之间的反复连接的自联想网络中的突触可塑性被认为能够存储情景记忆。情景记忆受损是阿尔茨海默病（AD）认知缺陷的早期表现。在APP/PS1小鼠模型的AD淀粉样变性，我们表明，联合长时程突触增强（LTP）被取消在CA 3锥体细胞在早期阶段。这是由上调的神经元腺苷A2 A受体（A2 AR）的激活引起的，而不是由NMDAR信号传导失调或树突棘形态改变引起的。在单个突触后神经元中，通过急性药理学抑制或由shRNA干扰驱动的下调来中和A2 AR，从而恢复关联性CA 3 LTP。因此，用A2 AR拮抗剂治疗可逆转一次试验记忆缺陷。这些结果提供了机制支持，以鼓励测试A2 AR拮抗剂在早期AD患者的治疗效果。 海马突触功能障碍是阿尔茨海默病的早期症状。在这里，作者发现腺苷A2 A受体在APP/PS1模型小鼠中上调，并且删除或阻断受体活性有助于减轻可塑性和记忆障碍。
Synaptic plasticity in the autoassociative network of recurrent connections among hippocampal CA3 pyramidal cells is thought to enable the storage of episodic memory. Impaired episodic memory is an early manifestation of cognitive deficits in Alzheimer's disease (AD). In the APP/PS1 mouse model of AD amyloidosis, we show that associative long-term synaptic potentiation (LTP) is abolished in CA3 pyramidal cells at an early stage. This is caused by activation of upregulated neuronal adenosine A2A receptors (A2AR) rather than by dysregulation of NMDAR signalling or altered dendritic spine morphology. Neutralization of A2AR by acute pharmacological inhibition, or downregulation driven by shRNA interference in a single postsynaptic neuron restore associative CA3 LTP. Accordingly, treatment with A2AR antagonists reverts one-trial memory deficits. These results provide mechanistic support to encourage testing the therapeutic efficacy of A2AR antagonists in early AD patients. Hippocampal synaptic dysfunctions are an early symptom of Alzheimer's disease. Here, the authors find adenosine A2A receptors are up-regulated in APP/PS1 model mice and that deleting or blocking receptor activity helps alleviate plasticity and memory impairments.