Astrocytic A2A Receptors: Novel Roles and Mechanisms in Alzheimers Disease

星形细胞 A2A 受体：在阿尔茨海默病中的新作用和机制

基本信息

批准号：
8516938
负责人：
ANNA GOLDSHMIDT ORR
金额：
$ 5.57万
依托单位：
J. DAVID GLADSTONE INSTITUTES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8516938
关键词：
Address Adenosine Adenosine A2A Receptor Affect Agonist Alzheimer&apos s Disease Amyloid beta-Protein Precursor Astrocytes Autopsy Behavior assessment Behavioral Brain Brain region Cognitive deficits Coupled Data Electrophysiology (science)Engineering Ensure Event Exhibits Glutamates Hippocampus (Brain)Human Image Impaired cognition Learning Lentivirus Vector Life Link Mediating Membrane Memory Mus Nerve Degeneration Neuroglia Neurologic Neuronal Dysfunction Neurons Pathogenesis Pathology Pathway interactions Patients Prevention strategy Process Purinergic P1 Receptors Research Research Project Grants Role Serine Signal Transduction Slice Structure Synapses Synaptic Transmission Synaptic plasticity Techniques Testing Time Training Transgenic Mice Wild Type Mouse Work base computerized data processing extracellular mouse model nervous system disorder new therapeutic target novel overexpression receptor receptor coupling research study success synaptic function

Address Adenosine Adenosine A2A Receptor Affect Agonist Alzheimer&apos s Disease Amyloid beta-Protein Precursor Astrocytes Autopsy Behavior assessment Behavioral Brain Brain region Cognitive deficits Coupled Data Electrophysiology (science)Engineering Ensure Event Exhibits Glutamates Hippocampus (Brain)Human Image Impaired cognition Learning Lentivirus Vector Life Link Mediating Membrane Memory Mus Nerve Degeneration Neuroglia Neurologic Neuronal Dysfunction Neurons Pathogenesis Pathology Pathway interactions Patients Prevention strategy Process Purinergic P1 Receptors Research Research Project Grants Role Serine Signal Transduction Slice Structure Synapses Synaptic Transmission Synaptic plasticity Techniques Testing Time Training Transgenic Mice Wild Type Mouse Work base computerized data processing extracellular mouse model nervous system disorder new therapeutic target novel overexpression receptor receptor coupling research study success synaptic function

展开

项目摘要

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.

描述（由申请人提供）：腺苷是大脑功能的有效调节剂。腺苷的积累激活腺苷受体A2A-R，从而调节神经元活性。在某些类型的神经元中，A2A-R的表达很高，但星形胶质细胞低。我们发现，阿尔茨海默氏病（AD）和AD小鼠模型的星形胶质细胞中A2A-R的表达异常高。死后人大脑中的A2A-R水平与AD病理的水平密切相关。基于这些意外的结果，我们假设星形胶质细胞A2A-R参与了AD发病机理。为了检验我们的假设，我们将在操纵星形胶质细胞A2A-R表达水平后检查小鼠与AD相关的认知功能障碍。我们还将研究星形胶质细胞A2A-R可能影响神经元功能的机制。通过细胞内GS耦合途径的A2A-R信号，与星形胶质细胞过程的缩回有关，这些过程丢失了在死后AD大脑和AD小鼠模型中。实际上，GS耦合信号传导的腺苷和活化剂都诱导培养的星形胶质细胞中的过程缩回。值得注意的是，星形胶质细胞缩回与神经元功能的变化有关。但是，很少有研究解决了星形胶质性缩回的原因或其在与广告相关的神经元功能障碍中的可能作用。我们将确定A2A-R触发者在星形胶质细胞中的回缩并改变神经元活性的GS耦合信号传导。总而言之，我们建议检查A2A-R的升高水平是否通过细胞内的GS耦合信号传导，诱导异常的星形胶质性回缩并导致与AD相关的神经元功能障碍。研究这种新型的星形胶质细胞 - 神经元相互作用可能会发现AD中星形胶质细胞和腺苷受体的新作用，并为减轻与广告相关的认知下降提供新的治疗靶标。这些研究还可能揭示了一种新的机制，通过该机制，星形胶质细胞调节神经元活性并有助于正常的脑功能。提出的目的和实验方法是由腺苷激活星形胶质细胞A2A-R并导致GS耦合细胞内信号传导的工作假设驱动的，这会诱导星形胶质细胞的形态变化和神经元活性的下游变化。各种技术将用于检验这一工作假设，包括小鼠的行为评估，实时延时共聚焦成像和电生理学。概述了替代策略，以确保在技术困难的情况下进行特别具有挑战性的实验。拟议的研究有望增强我们对正常脑功能的理解，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退行性和神经神经神经元相互作用领域的候选人提供严格的科学培训机会。