Knockout of Low-Density Lipoprotein Receptor-Related Protein 1 From Astrocytes in Adult Mice Accelerates Long-Term Functional Recovery After Ischemic Stroke

Purpose: Ischemic stroke is a primary cause of death and disability worldwide; however, therapeutic opportunities are limited. Astrocytes, a major class of caretaker glia in the brain, can significantly alter outcomes after stroke through multiple pathways. Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional receptor that can modulate cellular signaling through its interaction with a diverse array of signaling mediators; however, its role in astrocyte function is not well elucidated. We tested whether LRP1 in astrocytes could alter outcomes in both the acute phase (24 h) and chronic phase (3–9 months) after middle cerebral artery occlusion in mice. Methods: Astrocyte-specific Lrp1 knockout mice were generated by crossing Cx30-CreER^T2 mice with Lrp1-floxed mice. As controls, mice were compared to Cx30-CreER^T2 mice with wild-type Lrp1. Cre activation was induced by tamoxifen treatment at 2 months of age in all mice. At 3 months of age, male and female mice were subjected to either middle cerebral artery occlusion for 1 h or sham surgery. Mice underwent motor coordination testing, and tissues were harvested at 24 h, 7 days, 3 months, or 9 months post-surgery for subsequent histological analysis. Findings: We found that genetic knockout of Lrp1 in astrocytes worsened motor coordination in mice acutely after middle cerebral artery occlusion, but paradoxically improved long-term outcomes by 3 months after stroke. Notably, at 3 months post-stroke, loss of astrocyte LRP1 was associated with improved motor outcomes and reduced gliosis. Conclusion: Our results suggest that loss of astrocyte LRP1 accelerates recovery after ischemic stroke.