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

Research output: Contribution to journalArticlepeer-review

Abstract

Blood-brain barrier (BBB) endothelial cells lining the cerebral microvasculature maintain dynamic equilibrium between soluble amyloid-b (Ab) levels in the brain and plasma. The BBB dysfunction prevalent in Alzheimer disease contributes to the dysregulation of plasma and brain Ab and leads to the perturbation of the ratio between Ab42 and Ab40, the two most prevalent Ab isoforms in patients with Alzheimer disease. We hypothesize that BBB endothelium distinguishes between Ab40 and Ab42, distinctly modulates their trafficking kinetics between plasma and brain, and thereby contributes to the maintenance of healthy Ab42/Ab40 ratios. To test this hypothesis, we investigated Ab40 and Ab42 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 Ab40 and Ab42 (F-Ab40 and F-Ab42) were not significantly different on the abluminal side, the luminal uptake rate of F-Ab42 was substantially higher than F-Ab40. Since higher plasma Ab levels were shown to aggravate BBB dysfunction and trigger cerebrovascular disease, we systematically investigated the dynamic interactions of luminal [125I]Ab 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]Ab42 and its subsequent BBB transcytosis is significantly higher than [125I]Ab40. 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 Ab40 and Ab42, engender shifts in the Ab42/Ab40 ratio, and unleash downstream toxic effects. SIGNIFICANCE STATEMENT Dissecting the binding and uptake kinetics of Ab40 and Ab42 at the BBB endothelium will facilitate the estimation of Ab40 versus Ab42 exposure to the BBB endothelium and allow assessment of the risk of BBB dysfunction by monitoring Ab42 and Ab40 levels in plasma. This knowledge, in turn, will aid in elucidating the role of these predominant Ab 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.

PubMed: MeSH publication types

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

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