Transport pathways for clearance of human Alzheimer's amyloid β-peptide and apolipoproteins E and J in the mouse central nervous system

Amyloid β-peptide (Aβ) clearance from the central nervous system (CNS) maintains its low levels in brain. In Alzheimer's disease, Aβ accumulates in brain possibly because of its faulty CNS clearance and a deficient efflux across the blood-brain barrier (BBB). By using human-specific enzyme-linked immunosorbent assays, we measured a rapid 30 mins efflux at the BBB and transport via the interstitial fluid (ISF) bulk flow of human-unlabeled Aβ and of Aβ transport proteins, apolipoprotein E (apoE) and apoJ in mice. We show (i) Aβ40 is cleared rapidly across the BBB via low-density lipoprotein receptor-related protein (LRP)1 at a rate of 0.21 pmol/min g ISF or 6-fold faster than via the ISF flow; (ii) Aβ42 is removed across the BBB at a rate 1.9-fold slower compared with Aβ40; (iii) apoE, lipid-poor isoform 3, is cleared slowly via the ISF flow and across the BBB (0.03-0.04 pmol/min g ISF), and after lipidation its transport at the BBB becomes barely detectable within 30 mins; (iv) apoJ is eliminated rapidly across the BBB (0.16 pmol/min g ISF) via LRP2. Clearance rates of unlabeled and corresponding ¹²⁵I-labeled Aβ and apolipoproteins were almost identical, but could not be measured at low physiologic levels by mass spectrometry. Amyloid β-peptide 40 binding to apoE3 reduced its efflux rate at the BBB by 5.7-fold, whereas Aβ42 binding to apoJ enhanced Aβ42 BBB clearance rate by 83%. Thus, Aβ, apoE, and apoJ are cleared from brain by different transport pathways, and apoE and apoJ may critically modify Aβ clearance at the BBB.