Low-density lipoprotein receptor-related protein-1: a serial clearance homeostatic mechanism controlling Alzheimer's amyloid beta-peptide elimination from the brain

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 beta-peptide (A beta). According to the two-hit vascular hypothesis for AD, vascular damage precedes cerebrovascular and brain A beta accumulation (hit 1) which then further amplifies neurovascular dysfunction (hit 2) preceding neuro-degeneration. 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 A beta clearance including (i) cell-surface LRP1 at the blood-brain barrier and cerebrovascular cells mediating brain-to-blood A beta clearance (ii) circulating LRP1 providing a key endogenous peripheral 'sink' activity for plasma A beta which prevents free A beta access to the brain, and (iii) LRP1 in the liver mediating systemic A beta clearance. Pitfalls in experimental A beta 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.