Abstract 109: Depletion of Microglia Does Not Improve Functional Outcomes in Aged Mice After Transient Focal Ischemia

Abstract

Introduction: With aging, microglia acquire a dysfunctional phenotype characterized by dystrophic morphology, impaired phagocytosis, reduced motility, and an exaggerated response to injury. Microglia become pathologically activated with aging and play a detrimental role in age-associated cognitive decline and neurodegenerative diseases. Older mice exhibit a differential response to stroke and have worse outcomes despite smaller infarcts compared to young mice. Microglia from aged mice produce higher levels of reactive oxidative species and have an exaggerated inflammatory response after ischemic stroke. Hypothesis: We hypothesized that ablation of microglia would reduce the exaggerated neuroinflammatory responses in aged mice and loss of microglia would improve early recovery after ischemic stroke. Aged (18-19 months) male mice were fed a control chow diet (CD) or PLX5622 chow diet (PLXD) for 21 days. On day 22, 60-minute middle cerebral artery occlusion (MCAo) or sham surgery was performed. Twenty-four hours after MCAo, neurological deficit scores (NDS) and immunohistochemistry assessments, as well as flow cytometry, were performed. Results: There was a significant reduction in Iba1 + cells in striatum and cortex of the aged mice with PLX treatment: day 7 (p<0.05), day 14 (p<0.001), and day 21 (p<0.001) vs day 0. Twenty-four hours after MCAo, the NDS were not different between CD (3.0±0.18) and PLXD (2.92±0.21). However, an increase in infarct size was seen in the aged PLXD group compared to the aged CD group (p<0.05). After MCAo, there was an increase in infiltrating monocytes and neutrophils in both diet groups compared to their respective shams (p<0.05). However, an increase in infiltrating monocytes was observed in the PLXD MCAo vs. CD MCAo (p<0.0001) reflecting a differential monocyte response in animals without microglia. Additionally, a decrease in NeuN immunoreactivity was seen in the PLXD MCAo group compared to PLXD sham (p<0.01). GFAP + cells increased in PLXD sham group as compared to CD sham (p<0.05). Conclusions: Our results suggest that microglia are essential immune cells that surprisingly limit immune cell infiltration, decrease neuronal degeneration, and reduce neuroinflammation after ischemic stroke in aged mice.