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.
↵
This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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.
|
Log in using your username and password
Purchase access
In this issue
Amyloid-β 40/42 Uptake Kinetics at the Blood-Brain Barrier
