Astrocytic A2A Receptors: Novel Roles and Mechanisms in Alzheimers Disease

说明（由申请人提供）：腺苷是一种有效的脑功能调节剂。腺苷的积累激活腺苷受体A2 A-R，其调节神经元活性。A2 A-R在某些类型的神经元中表达较高，但在星形胶质细胞中表达较低。我们发现A2 A-R在阿尔茨海默病（AD）患者和AD小鼠模型中的星形胶质细胞中的表达异常高。死后人脑中A2 A-R水平与AD病理学水平密切相关。基于这些意想不到的结果，我们推测星形胶质细胞A2 A-R参与AD的发病机制。为了验证我们的假设，我们将检查AD相关的认知功能障碍的小鼠后，操纵星形胶质细胞A2 A-R的表达水平。我们还将研究星形胶质细胞A2 A-R可能影响神经元功能的机制。A2 A-R通过细胞内GS-偶联途径发出信号，并参与星形胶质细胞过程的收缩，这在死后AD脑和AD小鼠模型中丢失。事实上，腺苷和激活剂的GS-偶联信号诱导过程收缩培养的星形胶质细胞。值得注意的是，星形胶质细胞收缩与神经元功能的变化有关。然而，很少有研究涉及星形胶质细胞回缩的原因或其在AD相关神经元功能障碍中的可能作用。我们将确定A2 A-R的GS偶联信号是否触发星形胶质细胞的收缩并改变神经元的活动。总之，我们建议检查是否A2 A-R水平升高，通过细胞内GS-偶联信号，诱导异常星形胶质细胞回缩，并有助于AD相关的神经元功能障碍。研究这种新的星形胶质细胞-神经元相互作用可能会发现星形胶质细胞和腺苷受体在AD中的新作用，并为缓解AD相关的认知功能下降提供新的治疗靶点。这些研究还可能揭示星形胶质细胞调节神经元活动并有助于正常脑功能的新机制。 所提出的目标和实验方法是由腺苷激活星形胶质细胞A2 A-R并导致GS偶联的细胞内信号传导的工作假设驱动的，所述信号传导诱导星形胶质细胞的形态变化和神经元活性的下游变化。将使用多种技术来测试这一工作假设，包括小鼠行为评估，实时延时共聚焦成像和电生理学。概述了替代策略，以确保在特别具有挑战性的实验中遇到技术困难时取得成功。这项拟议中的研究有望增强我们对正常大脑功能的理解，并可能为预防或治疗AD的有效策略铺平道路。该研究计划还将为神经变性和神经胶质-神经元相互作用领域的候选人提供严格的科学培训机会。

DESCRIPTION (provided by applicant): Adenosine is a potent regulator of brain function. Accumulation of adenosine activates the adenosine receptor A2A-R, which modulates neuronal activity. Expression of A2A-R is high in certain types of neurons, but low in astrocytes. We found that expression of A2A-R is abnormally high in astrocytes in patients with Alzheimer's disease (AD) and in an AD mouse model. A2A-R levels in postmortem human brains strongly correlated with the levels of AD pathology. Based on these unexpected results, we hypothesize that astrocytic A2A-R is involved in AD pathogenesis. To test our hypothesis, we will examine AD-related cognitive dysfunction in mice after manipulating astrocytic A2A-R expression levels. We will also investigate the mechanisms by which astrocytic A2A-R may influence neuronal function. A2A-R signals through the intracellular Gs-coupled pathway and has been implicated in retraction of astrocytic processes, which are lost in postmortem AD brain and AD mouse models. Indeed, both adenosine and activators of Gs-coupled signaling induce process retraction in cultured astrocytes. Notably, astrocyte retraction is linked to changes in neuronal function. However, few studies have addressed the causes of astrocytic retraction or its possible role in AD-related neuronal dysfunction. We will determine whether Gs-coupled signaling by A2A-R triggers retraction in astrocytes and alters neuronal activity. In summary, we propose to examine whether elevated levels of A2A-R, through intracellular Gs-coupled signaling, induce aberrant astrocytic retraction and contribute to AD-related neuronal dysfunction. Investigating this novel astrocyte-neuron interaction may uncover new roles for astrocytes and adenosine receptors in AD and offer new therapeutic targets for alleviating AD-related cognitive decline. These studies may also reveal a novel mechanism by which astrocytes regulate neuronal activity and contribute to normal brain function. The proposed aims and experimental approaches are driven by the working hypothesis that adenosine activates astrocytic A2A-R and leads to Gs-coupled intracellular signaling, which induces morphological changes in astrocytes and downstream changes in neuronal activity. Diverse techniques will be used to test this working hypothesis, including behavioral assessment in mice, live time-lapse confocal imaging, and electrophysiology. Alternative strategies are outlined to ensure success in the event of technical difficulties with particularly challenging experiments. The proposed research promises to enhance our understanding of normal brain function and may pave the path towards an effective strategy for the prevention or treatment of AD. The research plan will also provide a rigorous scientific training opportunity for the candidate in the fields of neurodegeneration and glial-neuronal interactions.