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）发病机理中的作用在很大程度上被了解。几乎没有 知道星形胶质细胞如何在不同的反应状态下改变其功能/特性以及什么 后果在病理条件下导致这种变化。 jak/stat路径是 诱导星形胶质细胞反应性响应促炎细胞因子。主动jak/stat信号已经 在人类广告大脑和AD动物模型中观察到，在促进与广告相关的病理中起着至关重要的作用 认知在AD模型小鼠中定义。但是，如何在星形胶质细胞中激活JAK/STAT途径。 AD进展以及与广告相关的星形胶质细胞反应如何影响其他脑细胞以促进AD病理学 不清楚。由OSMR基因编码的OSM受体β（OSMRβ）是JAK/STAT的关键上游激活因子 IL-6细胞因子家族的成员Oncostatin M（OSM）刺激的途径。 值得注意的是，OSMR已被揭示为与疾病相关的突出星形胶质细胞（DAA）标记，而基因 编码其他jak/stat上游激活剂与daas没有特别关联，这表明 OSMRβ在星形胶质细胞中JAK/STAT途径的AD相关激活中起着独特的作用。我们的功能测试 表明OSMRβ的激活增加了星形胶质细胞中多个DAA标记的表达，而 OSMR的星形胶质细胞缺失（称为OSMRCKO），或使用OSM中和的OSMRβ信号的阻断 抗体，显着降低了Aβ诱导的DAA标记表达。这些数据表明OSMRβ播放 在启动与广告相关的星形胶质细胞反应性中起着至关重要的作用。此外，用OSM中和抗体处理 appnl-g-f敲门小鼠中的Aβ沉积减弱并提高了其认知表现，支持角色 OSM/OSMRβ在调节这些相关的过程中的。进一步支持OSMRβ的疾病相关性 在AD中，我们发现其水平在验尸广告大脑中升高。总的来说，我们的初步数据揭示了 新型的OSMRβ/JAK/Stat轴，在启动星形胶质细胞反应和促进与AD相关的方面起着至关重要的作用 病理和认知缺陷。我们的中心假设是OSMRβ/JAK/STAT轴的激活 诱导与AD相关的星形胶质细胞反应性驱动AD进展，OSM/OSMRβ信号代表 广告疗法的有吸引力的靶标。我们将以三个目标来检验这些假设。在AIM 1中，我们将检查 OSMRβ引起的JAK/STAT信号的分子特征，并确定其在诱导AD相关的作用 星形胶质细胞分化和异质性。在AIM 2中，我们将研究OSMRβ/JAK/Stat诱导的星形胶质细胞如何 反应性会导致星形胶质细胞以及神经元和小胶质细胞的多面功能障碍。在AIM 3中， 我们将测试阻断OSM/OSMRβ信号传导是否有效缓解与AD相关的病理学和 认知缺陷。成功完成拟议的研究将揭示有关的基本信息 与广告相关的星形胶质细胞反应性的异质性和功能影响，并为临床前洞察 靶向OSM/OSMRβ信号传导，以改善与AD相关的神经病理学和认知缺陷。