Distinct uptake kinetics of Alzheimer disease amyloid-b 40 and 42 at the blood-brain barrier endothelium

Blood-brain barrier (BBB) endothelial cells lining the cerebral microvasculature maintain dynamic equilibrium between soluble amyloid- β (A β) levels in the brain and plasma. The BBB dysfunction prevalent in Alzheimer disease contributes to the dysregulation of plasma and brain A β and leads to the perturbation of the ratio between A β42 and A β40, the two most prevalent A β isoforms in patients with Alzheimer disease. We hypothesize that BBB endothelium distinguishes between A β40 and A β42, distinctly modulates their trafficking kinetics between plasma and brain, and thereby contributes to the maintenance of healthy A β42/A β40 ratios. To test this hypothesis, we investigated A β40 and A β42 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 A β40 and A β42 (F-A β40 and F-A β42) were not significantly different on the abluminal side, the luminal uptake rate of F-A β42 was substantially higher than F-A β40. Since higher plasma A β levels were shown to aggravate BBB dysfunction and trigger cerebrovascular disease, we systematically investigated the dynamic interactions of luminal [ 125I]A β 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]A β42 and its subsequent BBB transcytosis is significantly higher than [ 125I]A β40. 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 A β40 and A β42, engender shifts in the A β42/A β40 ratio, and unleash downstream toxic effects. SIGNIFICANCE STATEMENT: Dissecting the binding and uptake kinetics of A β40 and A β42 at the BBB endothelium will facilitate the estimation of A β40 versus A β42 exposure to the BBB endothelium and allow assessment of the risk of BBB dysfunction by monitoring A β42 and A β40 levels in plasma. This knowledge, in turn, will aid in elucidating the role of these predominant A β isoforms in aggravating BBB dysfunction and cerebrovascular disease.