In vitro evidence that beta-amyloid peptide 1-40 diffuses across the blood-brain barrier and affects its permeability

Beta amyloid peptides are major insoluble constituents of amyloid fibrils i n senile plaques and cerebrovascular deposits, both characteristic of Alzhe imer disease (AD). Low concentrations of soluble forms of amyloid peptides are also present in normal CSF. We previously demonstrated that the 40 amin o acid form of soluble beta-amyloid peptide (sA beta) is rapidly cleared fr om rat CSF into blood. Herein we hypothesized that a saturable, outwardly d irected flux of this peptide occurs at the blood-brain barrier (BBB) and te sted whether supraphysiological (possibly pathological) concentrations of s A beta could alter the permeability of this barrier to a paracellular trace r, polyethylene glycol (PEG). Using an in vitro model of BBB, we showed cha t influx and efflux of sA beta were equal, modest (60%-160% greater than th at of PEG), and not saturable. These observations suggest that sA beta move d across the monolayer by a diffusional process, and not via a transporter PEG flux was doubled immediately after the luminal concentration of cold sA beta was raised to 5 mu M, and was doubled 150 min after the abluminal con centration of sA beta was increased to 5 mu M. Pathological elevations of s A beta concentration in plasma or brain interstitial fluid may, therefore, alter the permeability of brain capillaries in vivo.