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Abstract 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 ( hCTSD hi ) 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. hCTSD hi 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 hCTSD hi 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.
Li et al. (Fri,) studied this question.