Knockout of Low-Density Lipoprotein Receptor-Related Protein 1 From Astrocytes in Adult Mice Accelerates Long-Term...

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.

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.

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.

Our results suggest that loss of astrocyte LRP1 accelerates recovery after ischemic stroke.