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

摘要

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 due to its faulty CNS clearance and a deficient efflux across the blood-brain barrier (BBB). By using human specific ELISAs, we measured a rapid 30 min 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-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 than 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 min; (iv) apoJ is eliminated rapidly across the BBB (0.16 pmol/min/g ISF) via low density lipoprotein receptor related protein-2. Clearance rates of unlabeled and corresponding ¹²⁵I-labeled Aβ and apolipoproteins were almost identical, but could not be measured at low physiological levels by mass spectrometry. Aβ40 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.