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

Amyloid beta-peptide (A beta) clearance from the central nervous system (CNS) maintains its low levels in brain. In Alzheimer's disease, Ab 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 A beta and of A beta transport proteins, apolipoprotein E ( apoE) and apoJ in mice. We show ( i) A beta 40 is cleared rapidly across the BBB via low-density lipoprotein receptor- related protein ( LRP) 1 at a rate of 0.21pmol/ min g ISF or 6- fold faster than via the ISF flow; (ii) A beta 42 is removed across the BBB at a rate 1.9-fold slower compared with A beta 40; (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 I-125-labeled A beta and apolipoproteins were almost identical, but could not be measured at low physiologic levels by mass spectrometry. Amyloid b- peptide 40 binding to apoE3 reduced its efflux rate at the BBB by 5.7- fold, whereas A beta 42 binding to apoJ enhanced A beta 42 BBB clearance rate by 83%. Thus, A beta, apoE, and apoJ are cleared from brain by different transport pathways, and apoE and apoJ may critically modify Ab clearance at the BBB.