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

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.

[O2–04–01]: Clearance of Beta‐amyloid Is Facilitated by Apolipoprotein E and Circulating High‐density Lipoproteins in Bioengineered Human Vessels

“…By contrast, our experiments evaluated functional Ab and apoE interactions under a variety of conditions. Murine and human ECs also differentially clear Ab with a 30-fold increase of Ab uptake in mouse cells (Qosa et al, 2014). Together, these observations might explain the differences observed between previously published murine data and our human model.…”

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

“…Previous studies have suggested that ~60% of brain Aβ is cleared via transportation to the periphery 21,22 . Our group has demonstrated, in a mouse model of AD, that brain-derived Aβ can be physiologically cleared in the periphery, and that a singular peripheral system can remove ~40% of the Aβ produced in the brain 23 .…”

Serum concentration of beta amyloid peptide and the activity of angiotensin converting enzyme in alzheimers disease patients: search for a potential biomarker

“…On the other hand, Aβ circulating in the blood can influx into and/or efflux from the brain, through a receptor-mediated transport, mechanism by which Aβ crosses the blood brain barrier (BBB). [16][17] There are a wide variety of methodologies for the measurement of products of cellular processes in CSF, blood plasma and serum as biomarkers for the diagnosis of different diseases and disorders.…”