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.

The current understanding of Alzheimer’s disease (AD) beyond amyloid β (Aβ) depositions and tau tangles remains incomplete. Our proposed study will address the role of astrocytes, the most abundant cell type in the brain, in regulating AD pathogenesis and progression. Successful accomplishment of our study will pave the way for future development of novel therapeutic strategies to diminish the detrimental astrocyte response in AD.