High-density lipoprotein mimetic peptide 4F efficiently crosses the blood-brain barrier and modulates amyloid-β distribution between brain and plasma

Suresh K. Swaminathan, Andrew L. Zhou, Kristen M. Ahlschwede, Geoffry L. Curran, Val J. Lowe, Ling Li, Karunya K. Kandimalla

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Treatments to elevate high-density lipoprotein (HDL) levels in plasma have decreased cerebrovascular amyloid - β (A β) deposition and mitigated cognitive decline in Alzheimer disease (AD) transgenic mice. Since the major protein component of HDL particles, apolipoprotein A-I (ApoA-I), has very low permeability at the blood-brain barrier (BBB), we investigated 4F, an 18-amino-acid ApoA-I/HDL mimetic peptide, as a therapeutic alternative. Specifically, we examined the BBB permeability of 4F and its effects on [ 125I]A β trafficking from brain to blood and from blood to brain. After systemic injection in mice, the BBB permeability of [ 125I]4F, estimated as the permeability-surface area (PS) product, ranged between 2 and 5 × 10 -6 ml/g per second in various brain regions. The PS products of [ 125I]4F were ∼1000-fold higher compared with those determined for [ 125I]ApoA-I. Moreover, systemic infusion with 4F increased the brain efflux of intracerebrally injected [ 125I]A β42. Conversely, 4F infusion decreased the brain influx of systemically injected [ 125I]A β42. Interestingly, 4F did not significantly alter the brain influx of [ 125I]A β40. To corroborate the in vivo findings, we evaluated the effects of 4F on [ 125I]A β42 transcytosis across polarized human BBB endothelial cell (hCMEC/D3) monolayers. Treatment with 4F increased the abluminal-to-luminal flux and decreased the luminal-to-abluminal flux of [ 125I]A β42 across the hCMEC/D3 monolayers. Additionally, 4F decreased the endothelial accumulation of fluorescein-labeled A β42 in the hCMEC/D3 monolayers. These findings provide a mechanistic interpretation for the reductions in brain A β burden reported in AD mice after oral 4F administration, which represents a novel strategy for treating AD and cerebral amyloid angiopathy. SIGNIFICANCE STATEMENT: The brain permeability of the ApoA-I mimetic peptide 4F was estimated to be ∼1000-fold greater than ApoA-I after systemic injection of radiolabeled peptide/protein in mice. Further, 4F treatment increased the brain efflux of amyloid - β and also decreased its brain influx, as evaluated in mice and in blood-brain barrier cell monolayers. Thus, 4F represents a potential therapeutic strategy to mitigate brain amyloid accumulation in cerebral amyloid angiopathy and Alzheimer disease.

Original languageEnglish (US)
Pages (from-to)308-316
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume375
Issue number2
DOIs
StatePublished - Nov 1 2020

Bibliographical note

Funding Information:
This work was supported by the Minnesota Partnership for Biotechnology and Medical Genomics [Grant RF1-00056030] and by National Institutes of Health National Institute on Aging [Grant RF1-AG058081] and [Grant R21-AG056025]. 1S.K.S. and A.L.Z. contributed equally to this work. https://doi.org/10.1124/jpet.120.265876.

Publisher Copyright:
Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics

Keywords

  • Amyloid beta-Peptides/blood
  • Animals
  • Blood-Brain Barrier/metabolism
  • Mice
  • Peptide Fragments/blood
  • Peptides/metabolism
  • Protein Transport/drug effects

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Journal Article
  • Research Support, N.I.H., Extramural

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