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 ß (OSMRß), 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
OSMRß plays a unique role in AD-related activation of the JAK/STAT pathway in astrocytes. Our functional tests
showed that activation of OSMRß increased expression of multiple DAA markers in astrocytes, whereas
astrocytic deletion of Osmr (referred to as OsmrcKO), or blockade of OSMRß signaling using an OSM neutralizing
antibody, significantly reduced Aß-induced expression of DAA markers. These data suggest that OSMRß plays
a crucial role in initiating AD-related astrocyte reactivity. Moreover, treatment with the OSM neutralizing antibody
attenuated Aß deposition in AppNL-G-F knock-in mice and improved their cognitive performance, supporting a role
of OSM/OSMRß in modulating these AD-relevant processes. To further support the disease relevance of OSMRß
in AD, we found that its level was elevated in postmortem AD brains. Collectively, our preliminary data reveal a
novel OSMRß/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 OSMRß/JAK/STAT axis
induces AD-related astrocyte reactivity to drive AD progression and that OSM/OSMRß 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 OSMRß-initiated JAK/STAT signaling and determine its role in inducing AD-related
astrocyte differentiation and heterogeneity. In Aim 2, we will examine how OSMRß/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/OSMRß 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/OSMRß signaling for improvement of AD-related neuropathology and cognitive deficits.