The concerted amyloid-beta clearance of LRP1 and ABCB1/P-gp across the blood-brain barrier is linked by PICALM

Steffen E. Storck, Anika M.S. Hartz, Jessica Bernard, Andrea Wolf, André Kachlmeier, Anne Mahringer, Sascha Weggen, Jens Pahnke, Claus U. Pietrzik

Research output: Contribution to journalArticlepeer-review

90 Scopus citations

Abstract

The accumulation of neurotoxic amyloid-beta (Aβ) in the brain is a characteristic hallmark of Alzheimer's disease (AD). The blood-brain barrier (BBB) provides a large surface area and has been shown to be an important mediator for removal of brain Aβ. Both, the ABC transporter P-glycoprotein (ABCB1/P-gp) and the receptor low-density lipoprotein receptor-related protein 1 (LRP1) have been implicated to play crucial roles in Aβ efflux from brain. Here, with immunoprecipitation experiments, co-immunostainings and dual inhibition of ABCB1/P-gp and LRP1, we show that both proteins are functionally linked, mediating a concerted transcytosis of Aβ through endothelial cells. Late-onset AD risk factor Phosphatidylinositol binding clathrin assembly protein (PICALM) is associated with both ABCB1/P-gp and LRP1 representing a functional link and guiding both proteins through the brain endothelium. Together, our results give more mechanistic insight on Aβ transport across the BBB and show that the functional interplay of different clearance proteins is needed for the rapid removal of Aβ from the brain.

Original languageEnglish
Pages (from-to)21-33
Number of pages13
JournalBrain, Behavior, and Immunity
Volume73
DOIs
StatePublished - Oct 2018

Bibliographical note

Publisher Copyright:
© 2018 Elsevier Inc.

Keywords

  • ABC transporter B1/P-glycoprotein (ABCB1/P-gp)
  • Alzheimer's disease (AD)
  • Amyloid-beta (Aβ)
  • Blood-brain barrier (BBB)
  • Clearance
  • Endothelial cell
  • Endothelium
  • Low-density lipoprotein receptor-related protein 1 (LRP1)
  • Phosphatidylinositol-binding clathrin assembly protein (PICALM)
  • Transcytosis

ASJC Scopus subject areas

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience

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