Astrocytic OSMR/JAK/STAT signaling in AD

反应性星形胶质细胞在阿尔茨海默病(AD)发病机制中的作用仍未得到很大程度的研究。小才是 了解星形胶质细胞如何在不同的反应状态下改变其功能/特性 这些变化在病理条件下造成的后果。JAK/STAT途径是 诱导星形胶质细胞对促炎细胞因子的反应。活动的JAK/STAT信令已经 在人类AD脑和AD动物模型中观察到，并在促进AD相关病理过程中起着至关重要的作用 以及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进展和AD相关星形胶质细胞反应性如何影响其他脑细胞促进AD病理仍然存在 不清楚。Osm受体β(osmrβ)由osmr基因编码，是JAK/STAT的上游关键激活子。 肿瘤抑制素M(OSM)是IL-6细胞因子家族中的一员。 值得注意的是，osmr已被发现是一个显著的疾病相关星形胶质细胞(DAA)标记，而基因 编码其他JAK/STAT上游激活子与DAA没有明确的关联，这表明 OSMRβ在AD相关星形胶质细胞JAK/STAT通路的激活中起着独特的作用。我们的功能测试 结果显示，激活osmrDAA可增加星形胶质细胞多种β标志物的表达，而 OSMR的星形细胞缺失(称为OsmrcKO)，或使用OSM中和来阻断OSMRβ信号 抗体可显著降低Aβ诱导的DAA标志物的表达。这些数据表明，OSMRβ扮演着 在启动AD相关星形胶质细胞反应中起关键作用。此外，使用OSM中和抗体治疗 减轻Aβ在AppNL-G-F基因敲入小鼠中的沉积并改善其认知能力，起到支持作用 OSM/OSMRβ在调节这些AD相关过程中的作用。进一步支持OSMRβ与疾病的相关性 在AD中，我们发现其在死后AD脑中的水平升高。总体而言，我们的初步数据显示 新的OSMRJAK/STAT轴在启动星形胶质细胞反应和促进AD相关过程中起关键作用 病理学和认知缺陷。我们的中心假设是OSMRβ/JAK/STAT轴的激活 诱导AD相关星形胶质细胞的反应以推动AD的进展，而osm/osmrβ信号代表一种 治疗阿尔茨海默病有吸引力的靶点。我们将在三个目标上检验这些假设。在目标1中，我们将研究 OSMRβ启动的JAK/STAT信号的分子特征及其在AD相关诱导中的作用 星形胶质细胞分化与异质性。在目标2中，我们将研究osmrβ/JAK/STAT如何诱导星形胶质细胞 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害。在《目标3》中， 我们将测试阻断OSM/OSMRβ信号是否有效地改善AD相关的病理和 认知缺陷。成功完成拟议的研究将揭示以下方面的基本信息 AD相关星形胶质细胞反应性的异质性和功能影响 靶向osm/osmrβ信号通路改善AD相关神经病理和认知功能障碍。

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.