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病（AD）发病机制中的作用仍未得到充分研究。小是