Removal of Aβ Oligomers from the Blood: A Potential Therapeutic System for Alzheimer’s Disease

PURPOSE: Amyloid-β protein (Aβ) is one of the causative proteins of Alzheimer’s disease. We have been developing extracorporeal blood Aβ-removal systems as a method for enhancing Aβ clearance from the brain. We reported previously that medical adsorbents and hemodialyzers removed Aβ monomers from peripheral blood, which was associated with influx of Aβ monomers from the brain into the bloodstream. Our intent here was to develop a method to promote clearance of Aβ oligomers and to provide an estimate of the molecular size of intact Aβ oligomers in plasma. METHODS: Two hollow-fiber devices with different pore sizes (Membranes A and B) were evaluated as removers of Aβ oligomers with human plasma in vitro. The concomitant removal of Aβ oligomers and monomers was investigated by using Membrane B and hexadecyl alkylated cellulose beads or polysulfone hemodialyzers. Double-filtration plasmapheresis with Membrane A was investigated as an approach for the removal of plasma Aβ oligomers in humans. RESULTS: Aβ oligomers were effectively removed by both Membranes A and B. The increase of Aβ oligomers in plasma was observed just after the removal of plasma Aβ oligomers in humans. The intact molecular size of major Aβ oligomers in the plasma was estimated to be larger than albumin at approximately 60 kDa or more. Additionally, the concomitant removal of Aβ monomers and oligomers evoked dissociation of larger Aβ oligomers into smaller ones and monomers. CONCLUSION: Aβ oligomers were cleared from plasma both in vitro and in human subjects by using hollow-fiber membranes with large pores, indicating that their intact sizes were mostly larger than 60 kDa. Aβ oligomers in peripheral circulation were increased after some clearances in human. Further investigation will determine whether the Aβ oligomers detected in circulation after clearance were via influx from the brain.