Pharmacological depletion of microglia prevents vascular cognitive impairment in Ang II-induced hypertension

Abstract

Rationale: Hypertension is a major risk factor for cerebral small vessel disease, the most prevalent cause of vascular cognitive impairment. As we have shown, hypertension induced by a prolonged Ang II infusion is associated with increased permeability of the blood-brain barrier (BBB) and chronic activation of microglia. In this study we therefore aim to determine the contribution of microglia to hypertension-induced cognitive impairment in an experimental hypertension model by a pharmacological depletion approach. Methods: For this study, adult Cx3Cr1gfp/wtxThy1yfp/0 reporter mice were infused for 12 weeks with Angiotensin II or saline and subgroups were treated with PLX5622, a highly selective CSF-1R inhibitor. Systolic blood pressure (SBP) was measured via tail-cuff. Short- and long-term spatial memory were assessed during an Object Location task and a Morris Water Maze task (MWM). At the end of the study, microglia depletion efficacy and BBB leakages were assessed using flow cytometry and immunohistochemistry. Results: SBP, heart weight and carotid pulsatility were increased by Ang II and were not affected by PLX5622. Short-term memory was significantly impaired in Ang II hypertensive mice, but not in Ang II mice treated with PLX5622. Histological and flow cytometry analyses revealed almost complete ablation of microglia upon CSF1R inhibition, while brain resident perivascular macrophages, were reduced by 60%. Number and size of BBB leakages were increased in Ang II hypertensive mice, but not altered by PLX5622 treatment. Conclusion: Our results show that depletion of microglia, and less so PVMs, by CSF1R inhibition prevents short-term memory impairment in Ang II induced hypertensive mice. This novel finding supports the critical role of brain immune cells, and most in particular microglia, in the pathogenesis of hypertension-related cognitive impairment.