Circulatory pro-CTSD binds brain endothelial LRP1 to trigger its lysosomal degradation leading to amyloid beta clearance deficit in Alzheimer's disease mice.

INTRODUCTION: Clearance of cerebral Aβ was primarily mediated by the brain endothelial transporters including LRP1. The regulatory mechanism of LRP1 expression remained unclear. METHODS: LRP1 in brain endothelial cells treated with pro-CTSD were analyzed by western blot. Transgenic mice with high circulatory pro-CTSD (hCTSDhi) were generated to assess LRP1 levels and brain Aβ deposition by immunostaining and live-imaging. Internalization of pro-CTSD and its co-localization with LRP1 was analyzed using confocal and TIRF microscopy. RESULTS: Circulatory pro-CTSD is increased in the AD models. hCTSDhi mice exhibited reduced endothelial LRP1 and impaired Aβ clearance. Soluble pro-CTSD bound the Cluster II domain of LRP1, triggering LRP1 endocytosis and lysosomal degradation. Crossing hCTSDhi mice with AD models increased brain Aβ deposition and exaggerated cognitive deficit. DISCUSSION: Circulatory pro-CTSD triggered degradation of brain endothelial LRP1 to inhibit brain-to-blood Aβ clearance.