Distinct uptake kinetics of Alzheimer disease amyloid-b 40 and 42 at the blood-brain barrier endothelium

Nidhi Sharda, Kristen M. Ahlschwede, Geoffry L. Curran, Val J. Lowe, Karunya K. Kandimalla

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Abstract

Blood-brain barrier (BBB) endothelial cells lining the cerebral microvasculature maintain dynamic equilibrium between soluble amyloid- β (A β) levels in the brain and plasma. The BBB dysfunction prevalent in Alzheimer disease contributes to the dysregulation of plasma and brain A β and leads to the perturbation of the ratio between A β42 and A β40, the two most prevalent A β isoforms in patients with Alzheimer disease. We hypothesize that BBB endothelium distinguishes between A β40 and A β42, distinctly modulates their trafficking kinetics between plasma and brain, and thereby contributes to the maintenance of healthy A β42/A β40 ratios. To test this hypothesis, we investigated A β40 and A β42 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 A β40 and A β42 (F-A β40 and F-A β42) were not significantly different on the abluminal side, the luminal uptake rate of F-A β42 was substantially higher than F-A β40. Since higher plasma A β levels were shown to aggravate BBB dysfunction and trigger cerebrovascular disease, we systematically investigated the dynamic interactions of luminal [ 125I]A β 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]A β42 and its subsequent BBB transcytosis is significantly higher than [ 125I]A β40. 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 A β40 and A β42, engender shifts in the A β42/A β40 ratio, and unleash downstream toxic effects. SIGNIFICANCE STATEMENT: Dissecting the binding and uptake kinetics of A β40 and A β42 at the BBB endothelium will facilitate the estimation of A β40 versus A β42 exposure to the BBB endothelium and allow assessment of the risk of BBB dysfunction by monitoring A β42 and A β40 levels in plasma. This knowledge, in turn, will aid in elucidating the role of these predominant A β isoforms in aggravating BBB dysfunction and cerebrovascular disease.

Original languageEnglish (US)
Pages (from-to)482-490
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume376
Issue number3
DOIs
StatePublished - 2021

Bibliographical note

Funding Information:
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). 1Current affiliation: Department of Clinical Pharmacology and Pharmaco-metrics, Bristol-Myers Squibb, Princeton, New Jersey. 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. s This article has supplemental material available at jpet.aspetjournals.org.

Publisher Copyright:
© 2021 American Society for Pharmacology and Experimental Therapy. All rights reserved.

Keywords

  • Amyloid beta-Peptides/metabolism
  • Blood-Brain Barrier/metabolism
  • Cell Line
  • Endothelium/metabolism
  • Humans
  • Kinetics
  • Models, Biological
  • Peptide Fragments/metabolism
  • Protein Transport

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Journal Article

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