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 星形胶质细胞是成年大脑中最丰富和最多样化的神经胶质细胞，占70％ 神经胶质选区。星形胶质细胞执行正常脑功能的重要任务， 有助于各种神经系统疾病，包括神经退行性疾病，例如 阿尔茨海默氏病（AD）。但是，它们在健康和疾病中的作用仍然是一个谜。 最近，我们发现Sox9有助于星形胶质细胞介导的脑电路调节，以及 证明在人类AD样品中反应性星形胶质细胞中表达增加。 此外，在父母赠款中提供的初步数据中，我们发现Sox9具有老化 在维持海马星形胶质细胞的功能完整性方面的特定作用。在一起 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患者的多个大脑区域的神经元退化，这在很大程度上未知 星形胶质细胞如何促进AD的启动和发展以及星形细胞SOX9 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保持不确定。 在此提案中，我们将使用新生成的动物模型，使我们能够过表达或 在AD疾病进展的不同阶段，在星形胶质细胞中有选择地敲除SOX9。我们的 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 在AB斑块的积累中，在AD进展开始时，Sox9的敲除增强了 Ab斑块形成，而其过表达抑制了AB斑块的形成。这些结果 导致我们假设星形胶质细胞SOX9在星形胶质细胞和反应性中起着核心作用 AD发病机理期间的星形胶质细胞。为了测试这一点，我们提出了实验以确认Sox9 在人类广告大脑中的表达，并在早期使用Sox9的特定阶段操纵 疾病进展的中间阶段，以确定其如何影响AD发病机理和 相关的行为和电路水平改变（AIM 1）。了解Sox9如何影响 与AD发病机理相关的星形胶质细胞，我们将检查大量核心星形细胞 特性，包括形态学，Ca2+活性以及我们阶段与神经元的相互作用 - 特定，过表达和淘汰模型（AIM 2）。总之，我们的初步观察 表明星形胶质细胞-SOX9有助于AD发病机理，需要进一步研究 何时发挥这些作用及其如何影响AD的星形胶质细胞生理 进展。