Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Journal of Pharmacology and Experimental Therapeutics
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Journal of Pharmacology and Experimental Therapeutics

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Visit jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleMetabolism, Transport, and Pharmacogenomics

HDL mimetic peptide 4F efficiently crosses the blood-brain barrier and modulates amyloid beta distribution between brain and plasma

Suresh K Swaminathan, Andrew L Zhou, Kristen M Ahlschwede, Geoffry L Curran, Val J Lowe, Ling Li and Karunya K Kandimalla
Journal of Pharmacology and Experimental Therapeutics August 10, 2020, jpet.120.265876; DOI: https://doi.org/10.1124/jpet.120.265876
Suresh K Swaminathan
1 University of Minnesota;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andrew L Zhou
1 University of Minnesota;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kristen M Ahlschwede
2 Rosalind Franklin University of Medicine and Science;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Geoffry L Curran
3 Mayo Clinic
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Val J Lowe
3 Mayo Clinic
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ling Li
1 University of Minnesota;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Karunya K Kandimalla
1 University of Minnesota;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Info & Metrics
  • eLetters
  • PDF
Loading

Abstract

Treatments to elevate high-density lipoprotein (HDL) levels in plasma have decreased cerebrovascular amyloid beta (Aβ) deposition and mitigated cognitive decline in Alzheimer's 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 investigated the BBB permeability of 4F and its effect on 125I-Aβ trafficking from brain-to-blood and also 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 x 10-6 ml/g/s in various brain regions, which represents a ~1000 fold increase in permeability compared to 125I-ApoA-I. Moreover, systemic infusion with 4F increased the brain efflux of intracerebrally injected 125I-Aβ42. Conversely, 4F infusion decreased the brain influx of 125I-Aβ42. Interestingly, 4F did not significantly alter the brain influx of 125I-Aβ40. To corroborate the in vivo findings, we investigated the effects of 4F on 125I-Aβ42 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-Aβ42 across the hCMEC/D3 monolayers. Additionally, 4F decreased the endothelial accumulation of fluorescein-labeled Aβ42 in the hCMEC/D3 monolayers. These findings provide a mechanistic interpretation for the reductions in brain amyloid burden reported in AD mice after oral 4F administration, which represents a novel anti-amyloid strategy for treating AD patients.

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 beta and also decreased its brain influx, as evaluated in mice and in BBB cell monolayers. Thus, 4F represents a potential therapeutic strategy to mitigate brain amyloid accumulation in cerebral amyloid angiopathy and Alzheimer's disease.

  • Alzheimer's Disease
  • beta-amyloid
  • blood-brain barrier
  • CNS pharmacokinetics
  • drug disposition
  • lipoproteins
  • membrane transport
  • vascular permeability
  • The American Society for Pharmacology and Experimental Therapeutics
Next
Back to top

In this issue

Journal of Pharmacology and Experimental Therapeutics: 376 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 3
1 Mar 2021
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Journal of Pharmacology and Experimental Therapeutics article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
HDL mimetic peptide 4F efficiently crosses the blood-brain barrier and modulates amyloid beta distribution between brain and plasma
(Your Name) has forwarded a page to you from Journal of Pharmacology and Experimental Therapeutics
(Your Name) thought you would be interested in this article in Journal of Pharmacology and Experimental Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleMetabolism, Transport, and Pharmacogenomics

HDL mimetic peptide 4F efficiently crosses the blood-brain barrier and modulates amyloid beta distribution between brain and plasma

Suresh K Swaminathan, Andrew L Zhou, Kristen M Ahlschwede, Geoffry L Curran, Val J Lowe, Ling Li and Karunya K Kandimalla
Journal of Pharmacology and Experimental Therapeutics August 10, 2020, jpet.120.265876; DOI: https://doi.org/10.1124/jpet.120.265876

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Research ArticleMetabolism, Transport, and Pharmacogenomics

HDL mimetic peptide 4F efficiently crosses the blood-brain barrier and modulates amyloid beta distribution between brain and plasma

Suresh K Swaminathan, Andrew L Zhou, Kristen M Ahlschwede, Geoffry L Curran, Val J Lowe, Ling Li and Karunya K Kandimalla
Journal of Pharmacology and Experimental Therapeutics August 10, 2020, jpet.120.265876; DOI: https://doi.org/10.1124/jpet.120.265876
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • AOX1 Inhibition by Gefitinib, Erlotinib, and Metabolites
  • Catalytic Activity of CYP2C9 Variants
Show more Metabolism, Transport, and Pharmacogenomics

Similar Articles

  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About JPET
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0103 (Online)

Copyright © 2021 by the American Society for Pharmacology and Experimental Therapeutics