Semimechanistic Population Pharmacokinetic Modeling to Investigate Amyloid Beta Trafficking and Accumulation at the BBB Endothelium

Elevated exposure to toxic amyloid beta (Aβ) peptides and consequent blood-brain barrier (BBB) dysfunction are believed to promote vasculopathy in Alzheimer's disease (AD). However, the accumulation kinetics of different Aβ isoforms within the BBB endothelium and how it drives BBB dysfunction are not clearly characterized. Using single positron emission computed tomography (SPECT)-computed tomography (CT) dynamic imaging coupled with population pharmacokinetic modeling, we investigated the accumulation kinetics of Aβ40 and Aβ42 in the BBB endothelium. Brain clearance was quantified after intracerebral administration of 125I-Aβ, and BBB-mediated transport was shown to account for 54% of 125I-Aβ40 total clearance. A brain influx study demonstrated lower values of both maximal rate (Vmax) and Michaelis constant (Km) for 125I-Aβ42 compared to 125I-Aβ40. Validated by a transcytosis study in polarized human BBB endothelial cell (hCMEC/D3) monolayers, model simulations demonstrated impaired exocytosis was responsible for inefficient permeability and enhanced accumulation of Aβ42 in the BBB endothelium. Further, both isoforms were shown to disrupt the exocytosis machinery of BBB endothelial cells so that a vicious cycle could be generated. The validated model was able to capture changes in Aβ steady-state levels in plasma as well as the brain during AD progression and allowed us to predict the kinetics of Aβ accumulation in the BBB endothelium.