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.

抽象的 星形胶质细胞是成人大脑中最丰富、最多样化的神经胶质细胞，占大脑结构的 70% 神经胶质选区。星形胶质细胞执行正常大脑功能的基本任务 导致各种神经系统疾病，包括神经退行性疾病，例如 阿尔茨海默病（AD）。然而，它们在健康和疾病中的作用仍然是个谜。 最近，我们发现 Sox9 有助于星形胶质细胞介导的脑回路调节，并且 证明人类 AD 样本中反应性星形胶质细胞的表达增加。 此外，在母基金提供的初步数据中，我们发现 Sox9 具有老化- 在维持海马星形胶质细胞功能完整性方面的特殊作用。一起这些 观察促使我们进一步研究 Sox9 是否也在 AD 中发挥作用 发病。至关重要的是，尽管反应性星形胶质细胞与 AD 患者多个大脑区域的神经元退化，目前尚不清楚 星形胶质细胞如何促进 AD 的发生和进展以及星形胶质细胞 Sox9 的作用 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未确定。 在这个提案中，我们将使用新生成的动物模型，使我们能够过度表达或 在 AD 疾病进展的不同阶段，选择性地敲除星形胶质细胞中的 Sox9。我们的 对这些模型的初步研究表明星形胶质细胞 Sox9 起着至关重要的作用 AD 进展开始时 Ab 斑块的积累，其中 Sox9 的敲除增强了 Ab 斑块形成​​，而其过度表达则抑制 Ab 斑块形成​​。这些结果 引导我们假设星形胶质细胞 Sox9 在星形胶质细胞和反应性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。为了测试这一点，我们提出实验来确认 Sox9 人类 AD 大脑中的表达，并在早期阶段使用 Sox9 的阶段特定操作 以及疾病进展的中期阶段，以确定它如何影响 AD 发病机制， 相关的行为和回路水平的改变（目标 1）。了解 Sox9 的影响 星形胶质细胞与 AD 发病机制相关，我们将检查一系列核心星形胶质细胞 特性包括形态、Ca2+ 活性以及与我们阶段神经元的相互作用 - 特异性、过度表达和敲除模型（目标 2）。综上所述，我们的初步观察 表明星形胶质细胞-Sox9 有助于 AD 发病机制，值得进一步研究 了解它何时发挥这些作用以及它如何影响 AD 期间的星形胶质细胞生理学 进展。