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

Alzheimer's disease (AD) has a characteristic hallmark of amyloid-beta (A beta) accumulation in the brain. This accumulation of A beta has been related to its faulty cerebral clearance. Indeed, preclinical studies that used mice to investigate A beta clearance showed that efflux across blood brain barrier (BBB) and brain degradation mediate efficient A beta clearance. However, the contribution of each process to A beta clearance remains unclear. Moreover, it is still uncertain how species differences between mouse and human could affect A beta clearance. Here, a modified form of the brain efflux index method was used to estimate the contribution of BBB and brain degradation to A beta clearance from the brain of wild type mice. We estimated that 62% of intracerebrally injected I-125-A beta 40 is cleared across BBB while 38% is cleared by brain degradation. Furthermore, in vitro and in silico studies were performed to compare A beta clearance between mouse and human BBB models. Kinetic studies for A beta(40) disposition in bEnd3 and hCMEC/D3 cells, representative in vitro mouse and human BBB models, respectively, demonstrated 30-fold higher rate of I-125-A beta(40) 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 I-125-A beta(40) and the rate of each process. Established mechanistic model suggested significantly higher rates of A beta uptake and degradation in bEnd3 cells as rationale for the observed differences in I-125-A beta(40) disposition between mouse and human BBB models. In conclusion, current study demonstrates the important role of BBB in the clearance of A beta from the brain. Moreover, it provides insight into the differences between mouse and human BBB with regards to A beta clearance and offer, for the first time, a mathematical model that describes A beta clearance across BBB. (C). 2014 Elsevier Ltd. All rights reserved.