Astrocytic A2A Receptors: Novel Roles and Mechanisms in Alzheimer?s Disease

描述(申请人提供)：腺苷是一种强有力的大脑功能调节剂。腺苷的积累激活了腺苷受体A2a-R，该受体调节神经元的活动。A2A-R在某些类型的神经元中高表达，但在星形胶质细胞中低表达。我们发现，在阿尔茨海默病(AD)患者和AD小鼠模型中，A2A-R在星形胶质细胞中的表达异常高。人死后脑内A2A-R水平与AD病理水平密切相关。基于这些意想不到的结果，我们假设星形细胞A2A-R参与了AD的发病。为了验证我们的假设，我们将在操纵星形细胞A2A-R表达水平后，检查小鼠与AD相关的认知功能障碍。我们还将研究星形细胞A2A-R可能影响神经元功能的机制。A2A-R信号通过细胞内Gs偶联途径，并与星形细胞突起的收缩有关，而星形细胞突起在死后AD脑和AD小鼠模型中丢失。事实上，腺苷和Gs偶联信号激活剂都能诱导培养的星形胶质细胞突起回缩。值得注意的是，星形胶质细胞回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退缩的原因或其在AD相关神经元功能障碍中的可能作用。我们将确定A2A-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。综上所述，我们建议研究A2A-R水平升高是否通过细胞内Gs偶联信号诱导异常的星形胶质细胞收缩，并导致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揭示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和促进正常大脑功能的新机制。提出的目标和实验方法是基于腺苷激活星形胶质细胞A2a-R并导致Gs偶联的细胞内信号转导的工作假设，该信号转导导致星形胶质细胞的形态变化和下游神经元活动的变化。将使用多种技术来验证这一工作假说，包括对小鼠的行为评估、实时延时共聚焦成像和电生理学。概述了替代战略，以确保在发生技术困难时取得成功，特别是具有挑战性的试验。这项拟议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阿尔茨海默病铺平道路。该研究计划还将在神经退行性变和神经胶质-神经元相互作用领域为候选人提供严格的科学培训机会。 与公共健康相关：该研究项目将研究腺苷如何影响星形胶质细胞--大脑的非神经细胞--以及腺苷是否通过影响星形细胞功能来调节阿尔茨海默病小鼠模型的正常大脑活动和认知能力下降。这项研究项目有望揭示一种流行的神经疾病的正常大脑功能和大脑功能异常的可能原因的新信息。

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. PUBLIC HEALTH RELEVANCE: The research project will examine how astrocytes-the non-neuronal cells of the brain-are influenced by adenosine and whether adenosine, by affecting astrocytic function, regulates normal brain activity and cognitive decline in a mouse model of Alzheimer's disease. This research project promises to reveal new information about normal brain function and the possible causes of abnormal brain function in a prevalent neurological disease.