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

Alzheimers Dement. 2026 May;22(5):e71494. doi: 10.1002/alz.71494.

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 (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.

Keywords: Alzheimer's Disease; Amyloid beta clearance; Circulatory pro‐CTSD; LRP1; Lysosomal degradation.

MeSH terms

  • Alzheimer Disease* / metabolism
  • Alzheimer Disease* / pathology
  • Amyloid beta-Peptides* / metabolism
  • Animals
  • Brain* / metabolism
  • Brain* / pathology
  • Disease Models, Animal
  • Endothelial Cells* / metabolism
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-1* / metabolism
  • Lysosomes* / metabolism
  • Mice
  • Mice, Transgenic

Substances

  • Low Density Lipoprotein Receptor-Related Protein-1
  • Amyloid beta-Peptides
  • Lrp1 protein, mouse