Abstract DP168: Chronic Stroke Plasma Triggers Microglial Activation and Cognitive Decline in Young Mice

Introduction: Stroke is traditionally considered a localized brain injury. However, emerging evidence shows that stroke triggers lasting systemic changes associated with alterations in circulating factors, chronic brain inflammation, and cognitive decline. This study investigated whether plasma factors from aged mice in the chronic phase of ischemic stroke have the potential to induce cognitive impairment and microglial activation in healthy young recipient mice. Methods: Blood plasma was collected from aged (18-month-old) male and female C57Bl/6 mice at 6-months after 60-minute transient middle cerebral artery occlusion (tMCAO) or sham surgery, dialyzed to remove the anticoagulant, pooled by sex, and delivered retro-orbitally into young (12-week-old) sex-matched C57Bl/6 recipients (n=4-5/grp) over seven injections spaced three days apart across 4 weeks. During the fourth week, behavioral outcomes were assessed using open field test (OFT), novel object recognition test (NORT), and fear conditioning test (FCT). Flow cytometric analysis of brain tissue was performed to examine immune cell counts, microglial activation phenotype, cytokine production, senescence-associated markers, and mitochondrial activity. Results: Mice infused with chronic stroke plasma exhibited impairments in recognition memory (NORT) and associative memory (FCT), but no obvious change in locomotor activity (OFT). In the brain, stroke plasma caused pronounced microglial activation, evidenced by elevated Lamp1 expression, increased pro-inflammatory cytokine production, diminished mitochondrial activity, and increased senescence-related markers, particularly in females. Increased gliosis and senescent-like phenotypes were confirmed using immunohistochemistry. Conclusion: Our findings indicate that plasma factors derived from aged chronic stroke donor mice can drive cognitive impairments in recognition memory and fear learning of recipient mice. In the host brain, stroke plasma increases microglial activation status. These effects were more pronounced in females and highlight the long-lasting systemic consequences of circulating plasma factors on post-stroke cognitive decline. Our ongoing work aims to identify the molecular mediators of these effects through multi-omic profiling.