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 Pharmacogenetics

Distinct Uptake Kinetics of Alzheimer Disease Amyloid-β 40 and 42 at the Blood-Brain Barrier Endothelium

Nidhi Sharda, Kristen M. Ahlschwede, Geoffry L. Curran, Val J. Lowe and Karunya K. Kandimalla
Journal of Pharmacology and Experimental Therapeutics March 2021, 376 (3) 482-490; DOI: https://doi.org/10.1124/jpet.120.000086
Nidhi Sharda
Department of Pharmaceutics and the Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (N.S., K.K.K.); Department of Pharmaceutical Sciences, Rosalind Franklin University of Medicine and Science, College of Pharmacy, North Chicago, Illinois (K.M.A.); and Departments of Radiology (G.L.C., V.J.L.) and Neurology (G.L.C., K.K.K.), Mayo Clinic College of Medicine, Rochester, Minnesota
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kristen M. Ahlschwede
Department of Pharmaceutics and the Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (N.S., K.K.K.); Department of Pharmaceutical Sciences, Rosalind Franklin University of Medicine and Science, College of Pharmacy, North Chicago, Illinois (K.M.A.); and Departments of Radiology (G.L.C., V.J.L.) and Neurology (G.L.C., K.K.K.), Mayo Clinic College of Medicine, Rochester, Minnesota
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Geoffry L. Curran
Department of Pharmaceutics and the Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (N.S., K.K.K.); Department of Pharmaceutical Sciences, Rosalind Franklin University of Medicine and Science, College of Pharmacy, North Chicago, Illinois (K.M.A.); and Departments of Radiology (G.L.C., V.J.L.) and Neurology (G.L.C., K.K.K.), Mayo Clinic College of Medicine, Rochester, Minnesota
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Val J. Lowe
Department of Pharmaceutics and the Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (N.S., K.K.K.); Department of Pharmaceutical Sciences, Rosalind Franklin University of Medicine and Science, College of Pharmacy, North Chicago, Illinois (K.M.A.); and Departments of Radiology (G.L.C., V.J.L.) and Neurology (G.L.C., K.K.K.), Mayo Clinic College of Medicine, Rochester, Minnesota
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Karunya K. Kandimalla
Department of Pharmaceutics and the Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (N.S., K.K.K.); Department of Pharmaceutical Sciences, Rosalind Franklin University of Medicine and Science, College of Pharmacy, North Chicago, Illinois (K.M.A.); and Departments of Radiology (G.L.C., V.J.L.) and Neurology (G.L.C., K.K.K.), Mayo Clinic College of Medicine, Rochester, Minnesota
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF
Loading

Abstract

Blood-brain barrier (BBB) endothelial cells lining the cerebral microvasculature maintain dynamic equilibrium between soluble amyloid-β (Aβ) levels in the brain and plasma. The BBB dysfunction prevalent in Alzheimer disease contributes to the dysregulation of plasma and brain Aβ and leads to the perturbation of the ratio between Aβ42 and Aβ40, the two most prevalent Aβ isoforms in patients with Alzheimer disease. We hypothesize that BBB endothelium distinguishes between Aβ40 and Aβ42, distinctly modulates their trafficking kinetics between plasma and brain, and thereby contributes to the maintenance of healthy Aβ42/Aβ40 ratios. To test this hypothesis, we investigated Aβ40 and Aβ42 trafficking kinetics in hCMEC/D3 monolayers (human BBB cell culture model) in vitro as well as in mice in vivo. Although the rates of uptake of fluorescein-labeled Aβ40 and Aβ42 (F-Aβ40 and F-Aβ42) were not significantly different on the abluminal side, the luminal uptake rate of F-Aβ42 was substantially higher than F-Aβ40. Since higher plasma Aβ levels were shown to aggravate BBB dysfunction and trigger cerebrovascular disease, we systematically investigated the dynamic interactions of luminal [125I]Aβ peptides and their trafficking kinetics at BBB using single-photon emission computed tomography/computed tomography imaging in mice. Quantitative modeling of the dynamic imaging data thus obtained showed that the rate of uptake of toxic [125I]Aβ42 and its subsequent BBB transcytosis is significantly higher than [125I]Aβ40. It is likely that the molecular mechanisms underlying these kinetic differences are differentially affected in Alzheimer and cerebrovascular diseases, impact plasma and brain levels of Aβ40 and Aβ42, engender shifts in the Aβ42/Aβ40 ratio, and unleash downstream toxic effects.

SIGNIFICANCE STATEMENT Dissecting the binding and uptake kinetics of Aβ40 and Aβ42 at the BBB endothelium will facilitate the estimation of Aβ40 versus Aβ42 exposure to the BBB endothelium and allow assessment of the risk of BBB dysfunction by monitoring Aβ42 and Aβ40 levels in plasma. This knowledge, in turn, will aid in elucidating the role of these predominant Aβ isoforms in aggravating BBB dysfunction and cerebrovascular disease.

Footnotes

    • Received May 5, 2020.
    • Accepted December 2, 2020.
  • ↵1 Current affiliation: Department of Clinical Pharmacology and Pharmacometrics, Bristol-Myers Squibb, Princeton, New Jersey.

  • This work was supported by the Minnesota Partnership [Grant 15.31].

  • V.J.L. consults for Bayer Schering Pharma, Piramal Life Sciences, and Merck Research and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, and the NIH (NIA, NCI).

  • Primary laboratory of origin: (Kandimalla Laboratory, Department of Pharmaceutics and the Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, MN).

  • This work is part of the Ph.D. dissertation submitted to the University of Minnesota: Sharda N (2016) Trafficking of Amyloid beta protein at the Blood Brain Barrier: Novel Insights in Alzheimer’s Disease Pathogenesis. Doctoral dissertation, University of Minnesota, Minneapolis, Minnesota. Retrieved from the University of Minnesota Digital Conservancy, http://hdl.handle.net/11299/194548.

  • https://doi.org/10.1124/jpet.120.000086.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
View Full Text

JPET articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
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.
Distinct Uptake Kinetics of Alzheimer Disease Amyloid-β 40 and 42 at the Blood-Brain Barrier Endothelium
(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 Pharmacogenetics

Amyloid-β 40/42 Uptake Kinetics at the Blood-Brain Barrier

Nidhi Sharda, Kristen M. Ahlschwede, Geoffry L. Curran, Val J. Lowe and Karunya K. Kandimalla
Journal of Pharmacology and Experimental Therapeutics March 1, 2021, 376 (3) 482-490; DOI: https://doi.org/10.1124/jpet.120.000086

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 Pharmacogenetics

Amyloid-β 40/42 Uptake Kinetics at the Blood-Brain Barrier

Nidhi Sharda, Kristen M. Ahlschwede, Geoffry L. Curran, Val J. Lowe and Karunya K. Kandimalla
Journal of Pharmacology and Experimental Therapeutics March 1, 2021, 376 (3) 482-490; DOI: https://doi.org/10.1124/jpet.120.000086
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
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • OATP1B and PK of large lipophilic acids
  • PBPK Modeling of Chloroquine
Show more Metabolism, Transport, and Pharmacogenetics

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