Astrocytic OSMR/JAK/STAT signaling in AD

AD 中的星形胶质细胞 OSMR/JAK/STAT 信号传导

• 批准号: 10586851
• 负责人: Hongwei Qin
• 金额: $ 63.77万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586851
• 关键词: Address; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapy; Amyloid beta-Protein; Animal Disease Models; Astrocytes; Attenuated; Automobile Driving; Autopsy; Biology; Brain; Cells; Cognition; Cognitive deficits; Complex; Data; Development; Disease; Disease Progression; Family; Future; Genes; Goals; Heterogeneity; Human; Inflammatory; Interferons; Interleukin-6; Knock-in; Knock-in Mouse; Knowledge; Mediating; Microglia; Modeling; Molecular; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neurons; OSMR gene; Pathogenesis; Pathologic; Pathology; Pathway interactions; Phagocytosis; Play; Population; Process; Property; Regulation; Resolution; Role; Senile Plaques; Senility; Signal Transduction; Spatial Distribution; Testing; Therapeutic; abeta deposition; age related; beta amyloid pathology; brain cell; cell type; cognitive performance; cytokine; experience; functional disability; glial activation; improved; inflammatory marker; inhibitor; insight; member; mouse model; neuroinflammation; neuropathology; neurophysiology; neutralizing antibody; novel; novel therapeutic intervention; oncostatin M; pharmacologic; pre-clinical; receptor; response; tau Proteins; transcriptomics

The role of reactive astrocytes in Alzheimer’s disease (AD) pathogenesis remains largely understudied. Little is known about how astrocytes change their functions/properties under different reactive states and what consequences such changes cause under pathological conditions. The JAK/STAT pathway is a key player in inducing astrocyte reactivity in response to proinflammatory cytokines. Active JAK/STAT signaling has been observed in human AD brains and AD animal models, and plays a vital role in promoting AD-related pathology and cognitive deficits in AD model mice. However, how the JAK/STAT pathway is activated in astrocytes during AD progression and how AD-related astrocyte reactivity affects other brain cells to promote AD pathology remain unclear. OSM receptor β (OSMRβ), encoded by the Osmr gene, is a key upstream activator of the JAK/STAT pathway in response to stimulation by Oncostatin M (OSM), a member of the IL-6 family of cytokines. Significantly, Osmr has been revealed as a prominent disease-associated astrocyte (DAA) marker, while genes encoding other JAK/STAT upstream activators are not specifically associated with DAAs, suggesting that OSMRβ plays a unique role in AD-related activation of the JAK/STAT pathway in astrocytes. Our functional tests showed that activation of OSMRβ increased expression of multiple DAA markers in astrocytes, whereas astrocytic deletion of Osmr (referred to as OsmrcKO), or blockade of OSMRβ signaling using an OSM neutralizing antibody, significantly reduced Aβ-induced expression of DAA markers. These data suggest that OSMRβ plays a crucial role in initiating AD-related astrocyte reactivity. Moreover, treatment with the OSM neutralizing antibody attenuated Aβ deposition in AppNL-G-F knock-in mice and improved their cognitive performance, supporting a role of OSM/OSMRβ in modulating these AD-relevant processes. To further support the disease relevance of OSMRβ in AD, we found that its level was elevated in postmortem AD brains. Collectively, our preliminary data reveal a novel OSMRβ/JAK/STAT axis that plays a crucial role in initiating astrocyte reactivity and promoting AD-related pathology and cognitive deficits. Our central hypotheses are that activation of the OSMRβ/JAK/STAT axis induces AD-related astrocyte reactivity to drive AD progression and that OSM/OSMRβ signaling represents an attractive target for AD therapy. We will test these hypotheses in three aims. In Aim 1, we will examine the molecular features of OSMRβ-initiated JAK/STAT signaling and determine its role in inducing AD-related astrocyte differentiation and heterogeneity. In Aim 2, we will examine how OSMRβ/JAK/STAT-induced astrocyte reactivity leads to multi-faceted functional impairment of astrocytes as well as neurons and microglia. In Aim 3, we will test whether blocking OSM/OSMRβ signaling effectively ameliorates AD-related pathological and cognitive deficits. Successfully accomplishing the proposed studies will reveal fundamental information about the heterogeneity and functional impact of AD-related astrocyte reactivity and offer preclinical insight into targeting OSM/OSMRβ signaling for improvement of AD-related neuropathology and cognitive deficits.

反应性星形胶质细胞在阿尔茨海默氏病 (AD) 发病机制中的作用仍然没有得到充分研究。 了解星形胶质细胞在不同反应状态下如何改变其功能/特性以及什么 这些变化在病理条件下引起的后果 JAK/STAT 通路是其中的关键参与者。 诱导星形胶质细胞响应促炎细胞因子的反应性已被证实。 在人类 AD 大脑和 AD 动物模型中观察到，在促进 AD 相关病理过程中发挥着至关重要的作用 和 AD 模型小鼠的认知缺陷 然而，JAK/STAT 通路在星形胶质细胞中是如何被激活的。 AD 进展以及 AD 相关星形胶质细胞反应如何影响其他脑细胞以促进 AD 病理仍然存在 OSM 受体 β (OSMRβ) 由 Osmr 基因编码，是 JAK/STAT 的关键上游激活剂。 途径对制瘤素 M (OSM) 的刺激做出反应，制瘤素 M (OSM) 是细胞因子 IL-6 家族的成员。 值得注意的是，Osmr 已被揭示为一种重要的疾病相关星形胶质细胞 (DAA) 标记，而基因 编码其他 JAK/STAT 上游激活剂与 DAA 没有特定关联，这表明 OSMRβ 在星形胶质细胞中 JAK/STAT 通路的 AD 相关激活中发挥着独特的作用。 结果表明，OSMRβ 的激活增加了星形胶质细胞中多种 DAA 标记物的表达，而 Osmr 的星形细胞缺失（称为 OsmrcKO），或使用 OSM 中和阻断 OSMRβ 信号传导 抗体，显着降低了 Aβ 诱导的 DAA 标记物的表达，这些数据表明 OSMRβ 发挥了作用。 此外，OSM 中和抗体治疗在启动 AD 相关星形胶质细胞反应中发挥着至关重要的作用。 减少 AppNL-G-F 敲入小鼠中的 Aβ 沉积并改善其认知能力，支持作用 OSM/OSMRβ 在调节这些 AD 相关过程中的作用 进一步支持 OSMRβ 的疾病相关性。 在 AD 中，我们发现死后 AD 大脑中其水平升高。总的来说，我们的初步数据揭示了这一点。 新型 OSMRβ/JAK/STAT 轴在启动星形胶质细胞反应性和促进 AD 相关性方面发挥着至关重要的作用 我们的中心假设是 OSMRβ/JAK/STAT 轴的激活。 诱导 AD 相关的星形胶质细胞反应性以驱动 AD 进展，并且 OSM/OSMRβ 信号代表了一种 AD 治疗的有吸引力的目标。我们将在三个目标中检验这些假设。 OSMRβ启动的JAK/STAT信号传导的分子特征并确定其在诱导AD相关中的作用 在目标 2 中，我们将研究 OSMRβ/JAK/STAT 是如何诱导星形胶质细胞的。 在目标 3 中，反应性导致星形胶质细胞以及神经元和小胶质细胞的多方面功能损伤。 我们将测试阻断 OSM/OSMRβ 信号传导是否能有效改善 AD 相关的病理和 成功完成拟议的研究将揭示有关认知缺陷的基本信息。 AD 相关星形胶质细胞反应性的异质性和功能影响，并提供临床前见解 靶向 OSM/OSMRβ 信号传导以改善 AD 相关的神经病理学和认知缺陷。