Passage of human amyloid beta-protein 1-40 across the murine blood-brain barrier.

Previous studies have suggested that the amyloid beta-protein present in the brains of patients with Alzheimer's disease may be derived in part from peripheral blood. We determined that after IV injection of synthetic amyloid beta-protein 1-40 (A beta), labeled with radioactive 125I (I-A beta), radioactivity accumulated in the brains of mice by a nonsaturable mechanism. Radioactivity also accumulated in the brain after the i.v. injection of radioiodinated reverse amyloid beta-protein 40-1 (I-rA beta). Capillary depletion techniques, however, showed I-A beta to have a much greater degree of association with brain capillaries than I-rA beta. Acid precipitation of radioactivity in CSF samples and recovery from cortical homogenates suggested the presence of intact I-A beta within the CNS after peripheral administration. HPLC analysis of cortical homogenates confirmed the presence of intact I-A beta. Gel electrophoresis of the CSF acid precipitates and of the HPLC fractions further verified the presence of intact blood-derived I-A beta peptide in CNS. These results suggest that endogenous bloodborne A beta can enter the CNS after associating with the capillary endothelium to accumulate intact within the parenchymal and CSF spaces of the brain.