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Passage of human amyloid beta-protein 1-40 across the murine blood-brain barrier
L M Maness1, W A Banks, M B Podlisny
1Department of Neuroscience, Tulane University School of Medicine, New Orleans, Louisiana.
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.
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.