Low-density lipoprotein receptor-related protein-1: a serial clearance homeostatic mechanism controlling Alzheimer’s amyloid β-peptide elimination from the brain
Article first published online: 5 OCT 2010
© 2010 The Authors. Journal of Neurochemistry © 2010 International Society for Neurochemistry
Journal of Neurochemistry
Volume 115, Issue 5, pages 1077–1089, December 2010
How to Cite
Zlokovic, B. V., Deane, R., Sagare, A. P., Bell, R. D. and Winkler, E. A. (2010), Low-density lipoprotein receptor-related protein-1: a serial clearance homeostatic mechanism controlling Alzheimer’s amyloid β-peptide elimination from the brain. Journal of Neurochemistry, 115: 1077–1089. doi: 10.1111/j.1471-4159.2010.07002.x
- Issue published online: 2 NOV 2010
- Article first published online: 5 OCT 2010
- Accepted manuscript online: 20 SEP 2010 12:00AM EST
- Received July 15, 2010; revised manuscript received August 27, 2010; accepted September 3, 2010.
- Aβ clearance;
- Alzheimer’s disease;
- blood–brain barrier;
J. Neurochem. (2010) 115, 1077–1089.
Low-density lipoprotein receptor-related protein-1 (LRP1), a member of the low-density lipoprotein receptor family, has major roles in the cellular transport of cholesterol, endocytosis of 40 structurally diverse ligands, transcytosis of ligands across the blood–brain barrier, and transmembrane and nuclear signaling. Recent evidence indicates that LRP1 regulates brain and systemic clearance of Alzheimer’s disease (AD) amyloid β-peptide (Aβ). According to the two-hit vascular hypothesis for AD, vascular damage precedes cerebrovascular and brain Aβ accumulation (hit 1) which then further amplifies neurovascular dysfunction (hit 2) preceding neurodegeneration. In this study, we discuss the roles of LRP1 during the hit 1 and hit 2 stage of AD pathogenesis and describe a three-level serial LRP1-dependent homeostatic control of Aβ clearance including (i) cell-surface LRP1 at the blood–brain barrier and cerebrovascular cells mediating brain-to-blood Aβ clearance (ii) circulating LRP1 providing a key endogenous peripheral ‘sink’ activity for plasma Aβ which prevents free Aβ access to the brain, and (iii) LRP1 in the liver mediating systemic Aβ clearance. Pitfalls in experimental Aβ brain clearance measurements with the concurrent use of peptides/proteins such as receptor-associated protein and aprotinin are also discussed. We suggest that LRP1 has a critical role in AD pathogenesis and is an important therapeutic target in AD.