title: Amyloid-β concentration and structure influences the transport and immunomodulatory effects of IVIG.
abstract: Intravenous immunoglobulin (IVIG) contains anti-amyloid-β antibodies as well as antibodies providing immunomodulatory effects that may modify chronic inflammation in Alzheimer's disease. Answers to important questions about IVIG transport into the central nervous system and assessments of any impact amyloid-β has on this transport can be provided by in vitro models of the blood-brain barrier. In this study, amyloid-β[1-42] was pre-aggregated into fibrillar or oligomeric structures, and various concentrations were incubated in the brain side of the blood-brain barrier model, followed by IVIG administration in the blood side at the therapeutically relevant concentrations of 5 and 20 mg/mL. IVIG accumulated in the brain side at physiologically relevant levels, with amyloid-β pre-incubation increasing IVIG accumulation. The increased transport effect was dependent on amyloid-β structural form, amyloid-β concentration, and IVIG dose. IVIG was found to decrease monocyte chemotactic protein-1 levels 6.5-18% when low amyloid-β levels were present and increase levels 4.2-23% when high amyloid-β levels were present. Therefore, the presence, concentration, and structure of amyloid-β plays an important role in the effect of IVIG therapy in the brain. The mechanisms of action and transport across the blood-brain barrier (BBB) for an Alzheimer's disease therapeutic, intravenous immunoglobulin (IVIG), remain unknown. We investigated the transport of IVIG across endothelial cell BBB monolayers pre-incubated with amyloid-β peptides. We found that the concentration and structure of amyloid-β plays an important role in the effect of IVIG on BBB tightening and cytokine neutralization. (Note: Figure not drawn to scale.).
authors: Department of Chemical and Biomolecular Engineering and Delaware Biotechnology Institute, University of Delaware, Newark, Delaware, USA.
authors: Diane M
authors: DM
authors: Wuest
authors: Kelvin H
authors: KH
authors: Lee
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D001812:Blood-Brain Barrier / Q000378:metabolism; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000737:chemistry / Q000378:metabolism; D016756:Immunoglobulins, Intravenous / Q000378:metabolism* / Q000502:physiology; D007155:Immunologic Factors / Q000008:administration & dosage / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's disease; amyloid-β; blood-brain barrier; in vitro blood-brain barrier model; inflammation; intravenous immunoglobulin