title: Methods to monitor monocytes-mediated amyloid-beta uptake and phagocytosis in the context of adjuvanted immunotherapies.
abstract: Antibody-mediated capture of amyloid-beta (Aβ) in peripheral blood was identified as an attractive strategy to eliminate cerebral toxic amyloid in Alzheimer's disease (AD) patients and murine models. Alternatively, defective capacity of peripheral monocytes to engulf Aβ was reported in individuals with AD. In this report, we developed different approaches to investigate cellular uptake and phagocytosis of Aβ, and to examine how two immunological devices--an immunostimulatory Adjuvant System and different amyloid specific antibodies--may affect these biological events. Between one and thirteen months of age, APPswe X PS1.M146V (TASTPM) AD model mice had decreasing concentrations of Aβ in their plasma. In contrast, the proportion of blood monocytes containing Aβ tended to increase with age. Importantly, the TLR-agonist containing Adjuvant System AS01B primed monocytes to promote de novo Aβ uptake capacity, particularly in the presence of anti-Aβ antibodies. Biochemical experiments demonstrated that cells achieved Aβ uptake and internalization followed by Aβ degradation via mechanisms that required effective actin polymerization and proteolytic enzymes such as insulin-degrading enzyme. We further demonstrated that both Aβ-specific monoclonal antibodies and plasma from Aβ-immunized mice enhanced the phagocytosis of 1 μm Aβ-coated particles. Together, our data highlight a new biomarker testing to follow amyloid clearance within the blood and a mechanism of Aβ uptake by peripheral monocytes in the context of active or passive immunization, and emphasize on novel approaches to investigate this phenomenon.
authors.affiliation: GSK Vaccines, 525 Boulevard Cartier Ouest, Laval, Quebec, Canada, H7V 3S8; Neuroscience Laboratory, 2705, Boulevard Laurier, T-2-50, Department of Molecular Medicine, Centre Hospitalier Universitaire de Québec Research Center, Université Laval, Quebec City, Quebec, Canada, G1V 4G2.
authors.forename: Maxime
authors.initials: M
authors.lastname: Hallé
authors.affiliation: GSK Vaccines, 525 Boulevard Cartier Ouest, Laval, Quebec, Canada, H7V 3S8.
authors.forename: Pascale
authors.initials: P
authors.lastname: Tribout-Jover
authors.affiliation: GSK Vaccines, 525 Boulevard Cartier Ouest, Laval, Quebec, Canada, H7V 3S8.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lanteigne
authors.affiliation: GSK Vaccines, 525 Boulevard Cartier Ouest, Laval, Quebec, Canada, H7V 3S8.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Boulais
authors.affiliation: GSK Vaccines, 525 Boulevard Cartier Ouest, Laval, Quebec, Canada, H7V 3S8.
authors.forename: Julien R
authors.initials: JR
authors.lastname: St-Jean
authors.affiliation: GSK Vaccines, 525 Boulevard Cartier Ouest, Laval, Quebec, Canada, H7V 3S8.
authors.forename: Rachel
authors.initials: R
authors.lastname: Jodoin
authors.affiliation: GSK Vaccines, 525 Boulevard Cartier Ouest, Laval, Quebec, Canada, H7V 3S8.
authors.forename: Marie-Pier
authors.initials: MP
authors.lastname: Girouard
authors.affiliation: GSK Vaccines, 525 Boulevard Cartier Ouest, Laval, Quebec, Canada, H7V 3S8.
authors.forename: Florin
authors.initials: F
authors.lastname: Constantin
authors.affiliation: GSK Vaccines, 525 Boulevard Cartier Ouest, Laval, Quebec, Canada, H7V 3S8.
authors.forename: Annik
authors.initials: A
authors.lastname: Migneault
authors.affiliation: GSK Vaccines, Rue de l'Institut 89, B-1330 Rixensart, Belgium.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Renaud
authors.affiliation: GSK Vaccines, Rue de l'Institut 89, B-1330 Rixensart, Belgium.
authors.forename: Arnaud M
authors.initials: AM
authors.lastname: Didierlaurent
authors.affiliation: GSK Vaccines, 525 Boulevard Cartier Ouest, Laval, Quebec, Canada, H7V 3S8.
authors.forename: Corey P
authors.initials: CP
authors.lastname: Mallett
authors.affiliation: GSK Vaccines, 553 Old Corvallis Road, Hamilton, MT 59840, USA.
authors.forename: David
authors.initials: D
authors.lastname: Burkhart
authors.affiliation: GSK Vaccines, 525 Boulevard Cartier Ouest, Laval, Quebec, Canada, H7V 3S8.
authors.forename: Anthony
authors.initials: A
authors.lastname: Pilorget
authors.affiliation: GSK Vaccines, Rue de l'Institut 89, B-1330 Rixensart, Belgium.
authors.forename: Rémi
authors.initials: R
authors.lastname: Palmantier
authors.affiliation: GSK Vaccines, 525 Boulevard Cartier Ouest, Laval, Quebec, Canada, H7V 3S8. Electronic address: daniel.a.larocque@gsk.com.
authors.forename: Daniel
authors.initials: D
authors.lastname: Larocque
mesh_terms: D000199:Actins / Q000378:metabolism; D000276:Adjuvants, Immunologic; D000544:Alzheimer Disease / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D004195:Disease Models, Animal; D004338:Drug Combinations; D016130:Immunophenotyping; D007167:Immunotherapy; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism*; D010587:Phagocytosis / Q000276:immunology*; D055503:Protein Multimerization; D059748:Proteolysis; D012503:Saponins / Q000008:administration & dosage / Q000276:immunology; D014611:Vaccination
chemical_list: D000199:Actins; D000276:Adjuvants, Immunologic; D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D004338:Drug Combinations; D008050:Lipid A; D012503:Saponins; C000592464:adjuvant system 01
keywords: Adjuvant; Alzheimer's disease; Amyloid-beta; Aβ uptake; Monocyte; Phagocytosis; Vaccine