Lipoprotein receptor-related protein-1 mediates amyloid-beta-mediated cell death of cerebrovascular cells

Micha M M Wilhelmus, Irene Otte-Höller, Jos J J van Triel, Robert Veerhuis, Marion L C Maat-Schieman, Guojun Bu, Robert M W de Waal, Marcel M Verbeek

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113 Citations (Scopus)


Inefficient clearance of A beta, caused by impaired blood-brain barrier crossing into the circulation, seems to be a major cause of A beta accumulation in the brain of late-onset Alzheimer's disease patients and hereditary cerebral hemorrhage with amyloidosis Dutch type. We observed association of receptor for advanced glycation end products, CD36, and low-density lipoprotein receptor (LDLR) with cerebral amyloid angiopathy in both Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis Dutch type brains and increased low-density lipoprotein receptor-related protein-1 (LRP-1) expression by perivascular cells in cerebral amyloid angiopathy. We investigated if these A beta receptors are involved in A beta internalization and in A beta-mediated cell death of human cerebrovascular cells and astrocytes. Expression of both the LRP-1 and LDLR by human brain pericytes and leptomeningeal smooth muscle cells, but not by astrocytes, increased on incubation with A beta. Receptor-associated protein specifically inhibited A beta-mediated up-regulation of LRP-1, but not of LDLR, and receptor-associated protein also decreased A beta internalization and A beta-mediated cell death. We conclude that especially LRP-1 and, to a minor extent, LDLR are involved in A beta internalization by and A beta-mediated cell death of cerebral perivascular cells. Although perivascular cells may adapt their A beta internalization capacity to the levels of A beta present, saturated LRP-1/LDLR-mediated uptake of A beta results in degeneration of perivascular cells.

Original languageEnglish
Pages (from-to)1989-99
Number of pages11
JournalThe American Journal of Pathology
Issue number6
Publication statusPublished - Dec 2007


  • Aged
  • Aged, 80 and over
  • Alzheimer Disease
  • Amyloid beta-Peptides
  • Apoptosis
  • Blood Vessels
  • Blood-Brain Barrier
  • Brain
  • CD36 Antigens
  • Cerebral Amyloid Angiopathy, Familial
  • Female
  • Humans
  • Journal Article
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Male
  • Pericytes
  • Receptors, LDL
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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