Abstract Declines in vascular integrity are potential contributors to Alzheimer’s disease (AD) as these result in increased blood-brain barrier permeability and, as a consequence, accelerate neuroinflammation and cognitive impairment. Roundabout guidance receptor 4 (Robo4) is primarily expressed in endothelial cells and stabilizes the vasculature, and thus, has the potential to protect the brain in AD. To study the effect of Robo4 on neuroinflammation and cognitive function in the context of AD, we compared Robo4 knockout and wildtype mice crossed with mice with and without AD mutations (APP/tau). We found that the knockout of Robo4 led to greater astrocyte activation, as demonstrated by GFAP content, but this was dependent on the brain region studied. The knockout of Robo4 also led to greater activated microglia, as assessed by Iba1 content, but only in the presence of AD-related mutations. We found that AD mutations, but not Robo4, were associated with cognitive dysfunction measured by a nest-building test. In contrast, Robo4 deletion, but not AD mutations, was associated with impaired motor coordination. Lastly, Robo4 deletion was associated with greater arterial stiffness, but this trend did not reach statistical significance. In summary, these results demonstrate that Robo4 impacts neuroinflammation, motor coordination, and arterial stiffness, however, the impact on neuroinflammation is dependent on the presence/absence of AD-related mutations and the brain region examined.

Deletion of Robo4 worsens neuroinflammation and motor coordination in a mouse model of Alzheimer’s disease