title: Effective targeting of Aβ to macrophages by sonochemically prepared surface-modified protein microspheres.
abstract: Imbalanced homeostasis and oligomerization of the amyloid-β (Aβ) peptide in the brain are hallmarks of Alzheimer's disease (AD). Microglia and macrophages play a critical role in the etiology of AD either by clearing Aβ from the brain or inducing inflammation. Recent evidence suggests that clearance of Aβ by microglia/macrophages via the phagocytic pathway is defective in AD, which can contribute to the accumulation of Aβ in the brain. We have recently demonstrated that protein microspheres modified at their surface with multiple copies of an Aβ-recognition motif can strongly bind Aβ, inhibit its aggregation, and directly reduce its toxicity by sequestering it from the medium. Here, we describe how microsphere-bound Aβ can stimulate microglial cells and be phagocytosed through a mechanism that is distinct from that of Aβ removal and, thus, contribute to the clearance of Aβ, even by defective microglial cells. The phagocytosis was most effective, with microspheres having a diameter of <1 μm. The introduction of polyethylene glycol to the surface of the microspheres changed the kinetics of the phagocytosis. Moreover, while aggregated Aβ induced a significant inflammatory response that was manifested by the release of TNF-α, the microsphere-bound Aβ dramatically reduced the amount of cytokine released from microglial cells.
authors.affiliation: Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Richman
authors.forename: Alex
authors.initials: A
authors.lastname: Perelman
authors.forename: Asaf
authors.initials: A
authors.lastname: Gertler
authors.forename: Shai
authors.initials: S
authors.lastname: Rahimipour
mesh_terms: D016229:Amyloid beta-Peptides / Q000008:administration & dosage* / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D002460:Cell Line; D002478:Cells, Cultured; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000737:chemistry / Q000378:metabolism; D008863:Microspheres; D010587:Phagocytosis / Q000502:physiology; D012710:Serum Albumin, Bovine / Q000737:chemistry / Q000378:metabolism*; D013499:Surface Properties
chemical_list: D016229:Amyloid beta-Peptides; D012710:Serum Albumin, Bovine