TY - JOUR T1 - Distinct uptake kinetics of Alzheimer's disease amyloid beta 40 and 42 at the blood-brain barrier endothelium JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.120.000086 SP - JPET-AR-2020-000086 AU - Nidhi Sharda AU - Kristen M Ahlschwede AU - Geoffry L Curran AU - Val J Lowe AU - Karunya K. Kandimalla Y1 - 2020/01/01 UR - http://jpet.aspetjournals.org/content/early/2020/12/10/jpet.120.000086.abstract N2 - Blood-brain barrier (BBB) endothelial cells lining the cerebral microvasculature maintain the dynamic equilibrium between soluble amyloid beta (Aβ) levels in the brain and plasma. The BBB dysfunction prevalent in Alzheimer's disease contributes to the dysregulation of plasma and brain Aβ and leads to the perturbation of ratio between Aβ42 and Aβ40, two most prevalent Aβ isoforms in Alzheimer's patients. We hypothesize that BBB endothelium distinguishes between Aβ40 and Aβ42, distinctly modulates their trafficking kinetics between plasma and brain and thereby contributes to the maintenance of healthy Aβ42/Aβ40 ratios. To test this hypothesis, we investigated Aβ40 and Aβ42 trafficking kinetics in hCMEC/D3 monolayers (human BBB cell-culture model) in vitro as well as in mice in-vivo. While the rates of uptake of fluorescein labeled Aβ40 and Aβ42 (F-Aβ40 and F-Aβ42) were not significantly different on the abluminal side, the luminal uptake rate of F-Aβ42 was substantially higher than F-Aβ40. Since, higher plasma Aβ levels were shown to aggravate BBB dysfunction and trigger cerebrovascular disease, we systematically investigated the dynamic interactions of luminal 125I-Aβ peptides and their trafficking kinetics at BBB using single-photon-emission-computed-tomography/computed-tomography (SPECT/CT) imaging in mice. Quantitative modeling of the dynamic imaging data thus obtained showed that the rate of uptake of toxic 125I-Aβ42 and its subsequent BBB transcytosis is significantly higher than 125I-Aβ40. It is likely that the molecular mechanisms underlying these kinetic differences are differentially affected in Alzheimer's and cerebrovascular diseases, impact plasma and brain levels of Aβ40 and Aβ42, engender shifts in Aβ42/Aβ40 ratio, and unleash downstream toxic effects. Significance Statement Dissecting the binding and uptake kinetics of Aβ40 and Aβ42 at the BBB endothelium will facilitate the estimation Aβ40 versus Aβ42 exposure to the BBB endothelium and allow us to assess the risk of BBB dysfunction by monitoring Aβ42 and Aβ40 levels in the plasma. This knowledge, in turn, will aid in elucidating the role of these predominant Aβ isoforms in aggravating BBB dysfunction and cerebrovascular disease. ER -