Clearance of Alzheimer's amyloid-β1-40 peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier

M. Shibata, S. Yamada, S. Ram Kumar, M. Calero, J. Bading, B. Frangione, D. M. Holtzman, C. A. Miller, D. K. Strickland, J. Ghiso, B. V. Zlokovic

Research output: Contribution to journalArticlepeer-review

1085 Scopus citations

Abstract

Elimination of amyloid-β peptide (Aβ) from the brain is poorly understood. After intracerebral microinjections in young mice, 125I-Aβ1-40 was rapidly removed from the brain (t1/2 ≤ 25 minutes), mainly by vascular transport across the blood-brain barrier (BBB). The efflux transport system for Aβ1-40 at the BBB was half saturated at 15.3 nM, and the maximal transport capacity was reached between 70 nM and 100 nM. Aβ1-40 clearance was substantially inhibited by the receptor-associated protein, and by antibodies against LDL receptor-related protein-1 (LRP-1) and α2-macroglobulin (α2M). As compared to adult wild-type mice, clearance was significantly reduced in young and old apolipoprotein E (apoE) knockout mice, and in old wild-type mice. There was no evidence that Aβ was metabolized in brain interstitial fluid and degraded to smaller peptide fragments and amino acids before its transport across the BBB into the circulation. LRP-1, although abundant in brain microvessels in young mice, was downregulated in older animals, and this downregulation correlated with regional Aβ accumulation in brains of Alzheimer's disease (AD) patients. We conclude that the BBB removes Aβ from the brain largely via age-dependent, LRP-1-mediated transport that is influenced by α2M and/or apoE, and may be impaired in AD.

Original languageEnglish
Pages (from-to)1489-1499
Number of pages11
JournalJournal of Clinical Investigation
Volume106
Issue number12
DOIs
StatePublished - 2000

Fingerprint

Dive into the research topics of 'Clearance of Alzheimer's amyloid-β1-40 peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier'. Together they form a unique fingerprint.

Cite this