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Differences in amyloid-β clearance across mouse and human blood-brain barrier models: kinetic analysis and mechanistic modeling.

Qosa, Hisham; Abuasal, Bilal S.; Romero, Ignacio A.; Weksler, Babette; Couraud, Pierre-Oliver; Keller, Jeffrey N. and Kaddoumi, Amal (2014). Differences in amyloid-β clearance across mouse and human blood-brain barrier models: kinetic analysis and mechanistic modeling. Neuropharmacology, 79 pp. 668–678.

DOI (Digital Object Identifier) Link: https://doi.org/10.1016/j.neuropharm.2014.01.023
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Abstract

Alzheimer's disease (AD) has a characteristic hallmark of amyloid-β (Aβ) accumulation in the brain. This accumulation of Aβ has been related to its faulty cerebral clearance. Indeed, preclinical studies that used mice to investigate Aβ clearance showed that efflux across blood-brain barrier (BBB) and brain degradation mediate efficient Aβ clearance. However, the contribution of each process to Aβ clearance remains unclear. Moreover, it is still uncertain how species differences between mouse and human could affect Aβ clearance. Here, a modified form of the brain efflux index method was used to estimate the contribution of BBB and brain degradation to Aβ clearance from the brain of wild type mice. We estimated that 62% of intracerebrally injected 125I-Aβ40 is cleared across BBB while 38% is cleared by brain degradation. Furthermore, in vitro and in silico studies were performed to compare Aβ clearance between mouse and human BBB models. Kinetic studies for Aβ40 disposition in bEnd3 and hCMEC/D3 cells, representative in vitro mouse and human BBB models, respectively, demonstrated 30-fold higher rate of 125I-Aβ40 uptake and 15-fold higher rate of degradation by bEnd3 compared to hCMEC/D3 cells. Expression studies showed both cells to express different levels of P-glycoprotein and RAGE, while LRP1 levels were comparable. Finally, we established a mechanistic model, which could successfully predict cellular levels of 125I-Aβ40 and the rate of each process. Established mechanistic model suggested significantly higher rates of Aβ uptake and degradation in bEnd3 cells as rationale for the observed differences in 125I-Aβ40 disposition between mouse and human BBB models. In conclusion, current study demonstrates the important role of BBB in the clearance of Aβ from the brain. Moreover, it provides insight into the differences between mouse and human BBB with regards to Aβ clearance and offer, for the first time, a mathematical model that describes Aβ clearance across BBB.

Item Type: Journal Item
Copyright Holders: 2014 Elsevier Ltd.
ISSN: 1873-7064
Project Funding Details:
Funded Project NameProject IDFunding Body
Institutional Development Award (IDeA)P20GM103424National Institute of General Medical Sciences of the National Institutes of Health
Keywords: Amyloid-β; blood-brain barrier; clearance; mechanistic model
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
Item ID: 39570
Depositing User: Ignacio A Romero
Date Deposited: 25 Feb 2014 15:59
Last Modified: 07 Dec 2018 10:21
URI: http://oro.open.ac.uk/id/eprint/39570
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