Defining Roles for Astrocyte Subpopulations in the Aging Brain

定义星形胶质细胞亚群在衰老大脑中的作用

• 批准号: 10708356
• 负责人: Benjamin Deneen
• 金额: $ 32.76万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708356
• 关键词: Adult; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Animal Model; Astrocytes; Behavioral; Brain; Brain region; Data; Disease; Disease Progression; Health; Hippocampus; Human; Investigation; Knock-out; Mediating; Modeling; Morphology; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Pathogenesis; Physiology; Play; Property; Regulation; Role; Sampling; Testing; aging brain; experimental study; insight; nervous system disorder; overexpression; parent grant; response; transcription factor

Abstract Astrocytes are the most abundant and diverse glial cells in the adult brain, comprising 70% of the glial constituency. Astrocytes perform essential tasks for normal brain function and contribute to various neurological disorders, including neurodegenerative diseases such as Alzheimer's disease (AD). However, their role in health and disease remains a mystery. Recently, we found that Sox9 contributes to astrocyte-mediated regulation of brain circuits, and demonstrated increased expression in reactive astrocytes in the human AD samples. Furthermore, in preliminary data presented in the parent grant we found that Sox9 has an aging- specific role in maintaining the functional integrity of hippocampal astrocytes. Together these observation prompted us to further investigate whether Sox9 also plays a role in AD pathogenesis. Critically, although the reactive astrocytes are closely associated with degenerating neurons across multiple brain regions in patients with AD, it is largely unknown how astrocytes contribute to the initiation and progression of AD and how astrocytic Sox9 regulates functions of astrocytes and reactive astrocytes in this context also remains undefined. In this proposal, we will use newly generated animal models that enable us to overexpress or knockout Sox9 selectively in astrocytes, during different stages of AD disease progression. Our preliminary studies with these models demonstrated that astrocytic Sox9 plays an essential role in Ab plaque accumulation at the onset of AD progression, where knockout of Sox9 enhanced Ab plaque formation, while its overexpression suppressed Ab plaque formation. These results lead us to the hypothesis that astrocytic Sox9 plays a central role in astrocytes and reactive astrocytes during AD pathogenesis. To test this, we propose experiments to confirm Sox9 expression in the human AD brain and to use stage specific manipulations of Sox9 during early- and middle- stages of disease progression to determine how it impacts AD pathogenesis and associated behavioral- and circuit- levels alterations (Aim 1). To understand how Sox9 impacts astrocytes associated with AD pathogenesis, we will examine a host of core astrocytic properties including morphology, Ca2+ activity, and interactions with neurons in our stage- specific, overexpression and knockout models (Aim 2). In sum, our preliminary observations suggests that astrocytic-Sox9 contributes to AD pathogenesis, warranting further investigation into when it exerts these effects and how it impacts astrocyte physiology across AD progression.

摘要 星形胶质细胞是成人大脑中最丰富和多样的神经胶质细胞，占脑胶质细胞的70%。 神经胶质选民星形胶质细胞执行正常脑功能的基本任务， 导致各种神经系统疾病，包括神经退行性疾病， 阿尔茨海默病（AD）。然而，它们在健康和疾病中的作用仍然是一个谜。 最近，我们发现Sox 9有助于星形胶质细胞介导的脑回路调节， 在人AD样品中，在反应性星形胶质细胞中的表达增加。 此外，在父母补助金中提供的初步数据中，我们发现Sox 9具有老化- 在维持海马星形胶质细胞功能完整性中的特定作用。综合这些 这一观察促使我们进一步研究Sox 9是否也在AD中发挥作用 发病机制重要的是，尽管反应性星形胶质细胞与 在AD患者的多个大脑区域中，神经元变性在很大程度上是未知的， 星形胶质细胞如何参与AD的发生和发展以及星形胶质细胞Sox 9 在这种情况下调节星形胶质细胞和反应性星形胶质细胞的功能也仍然不清楚。 在这项提案中，我们将使用新产生的动物模型，使我们能够过度表达或 在AD疾病进展的不同阶段，选择性地在星形胶质细胞中敲除Sox 9。我们 对这些模型的初步研究表明，星形胶质细胞Sox 9发挥着重要作用， 在AD进展开始时的Ab斑块积累中，Sox 9敲除增强了 Ab空斑形成，而其过表达抑制Ab空斑形成。这些结果 这使我们假设星形胶质细胞Sox 9在星形胶质细胞中起着核心作用， AD发病机制中的星形胶质细胞。为了验证这一点，我们提出了实验来证实Sox 9 在人AD脑中的表达，并在早期AD中使用Sox 9的阶段特异性操作。 和疾病进展的中期阶段，以确定其如何影响AD发病机制， 相关的行为和电路水平的改变（目标1）。了解Sox 9如何影响 与AD发病机制相关的星形胶质细胞，我们将研究一系列核心星形胶质细胞， 包括形态学，Ca 2+活性，以及与我们阶段神经元的相互作用- 特异性、过表达和敲除模型（Aim 2）。总之，我们的初步观察 提示星形胶质细胞-Sox 9参与AD的发病机制， 研究它何时发挥这些作用，以及它如何影响AD患者的星形胶质细胞生理学 进展