Passage of human amyloid β-protein 1–40 across the murine blood-brain barrier

Abstract

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