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.