The origin of amyloid β (Aβ) deposited in brain and cerebral blood vessels of patients with Alzheimer′ s Disease (AD) is not known. In this study, we tested whether soluble Aβ (sAβ) can cross the blood-brain barrier (BBB). An in vivo vascular brain perfusion model and capillary depletion technique in guinea-pigs were used to determine cerebral capillary sequestration and blood-brain transport of a synthetic peptide identical with residues 1-40 (SP-40) of Aβ. A saturable, specific binding of SP-40 has been demonstrated at the luminal side of the BBB, with the K d of 25±2 nM, and B max of 188±11 fmol/min/g of isolated microvessels. A specific transcellular BBB transport of SP-40 into brain parenchyma exhibited the K m of 49±10 nM, and V max of 111±19 fmol/min/g of capillary depleted brain. We concluded that the BBB has the capability to control the cerebrovascular sequestration and blood-to-brain transport of circulating sAβ. Hence, sAβ can contribute to both cerebrovascular and parenchymal amyloid formation.