title: ImmunoPEGliposome-mediated reduction of blood and brain amyloid levels in a mouse model of Alzheimer's disease is restricted to aged animals.
abstract: The accumulation of extracellular amyloid-beta (Aβ) and intracellular neurofibrillary tangles (hyper-phosphorylated Tau) in the brain are two major neuropathological hallmarks of Alzheimer's disease (AD). Active and passive immunotherapy may limit cerebral Aβ deposition and/or accelerate its clearance. With the aid of a newly characterized monoclonal anti-Aβ antibody we constructed immunoPEGliposomes with high avidity for capturing Aβ in the periphery. The functionality of these vesicles in modulating Aβ uptake by both human brain capillary endothelial hCMEC/D3 cells (suppressing uptake) and THP-1 phagocytes (stimulating uptake) was confirmed in vitro. The multivalent immunoliposomes dramatically reduced circulating and brain levels of Aβ1-40, and particularly Aβ1-42, in "aged" (16 month-old), but not "adult" (10 month-old) APP/PS1 transgenic mice on repeated intraperitoneal administration. Furthermore, the immunoPEGliposome-mediated reduction in amyloidosis correlated with lower levels of glial fibrillary acidic protein (GFAP) and reactive glia (GFAP-positive cells). This treatment also lowered the ratio of phosphorylated Tau to total Tau. The therapeutic efficacy of immunoliposome treatment was superior to free monoclonal antibody administration (at an equivalent antibody dose). The potential mechanisms and significance of age-dependent immunoliposome therapy in AD is discussed.
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), C/ Nicolás Cabrera 1, Universidad Autónoma Madrid, 28049 Madrid, Spain; Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), C/ Nicolás Cabrera 1, Universidad Autónoma Madrid, 28049 Madrid, Spain.
authors.forename: Lara
authors.initials: L
authors.lastname: Ordóñez-Gutiérrez
authors.affiliation: STAB VIDA LDA Madan Parque, Rua dos Inventores, 2825-182 Caparica, Portugal.
authors.forename: Adrián
authors.initials: A
authors.lastname: Posado-Fernández
authors.affiliation: Centre for Pharmaceutical Nanotechnology and Nanotoxicology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark; Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran.
authors.forename: Davoud
authors.initials: D
authors.lastname: Ahmadvand
authors.affiliation: Centre for Pharmaceutical Nanotechnology and Nanotoxicology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Barbara
authors.initials: B
authors.lastname: Lettiero
authors.affiliation: Centre for Pharmaceutical Nanotechnology and Nanotoxicology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Linping
authors.initials: L
authors.lastname: Wu
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), C/ Nicolás Cabrera 1, Universidad Autónoma Madrid, 28049 Madrid, Spain; Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), C/ Nicolás Cabrera 1, Universidad Autónoma Madrid, 28049 Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Antón
authors.affiliation: STAB VIDA LDA Madan Parque, Rua dos Inventores, 2825-182 Caparica, Portugal.
authors.forename: Orfeu
authors.initials: O
authors.lastname: Flores
authors.affiliation: Centre for Pharmaceutical Nanotechnology and Nanotoxicology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark; NanoScience Centre, Faculty of Science, University of Copenhagen, DK-2100 Copenhagen Ø, Denmark; School of Medicine, Pharmacy and Health, Durham University, Stockton-on-Tees TS17 6BH, UK. Electronic address: moein.moghimi@gmail.com.
authors.forename: Seyed Moein
authors.initials: SM
authors.lastname: Moghimi
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), C/ Nicolás Cabrera 1, Universidad Autónoma Madrid, 28049 Madrid, Spain; Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), C/ Nicolás Cabrera 1, Universidad Autónoma Madrid, 28049 Madrid, Spain. Electronic address: fwandosell@cbm.csic.es.
authors.forename: Francisco
authors.initials: F
authors.lastname: Wandosell
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D008081:Liposomes / Q000737:chemistry*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011092:Polyethylene Glycols / Q000737:chemistry; D016896:Treatment Outcome
chemical_list: D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D008081:Liposomes; D011092:Polyethylene Glycols
keywords: APP/PS1 mouse; Amyloidosis; Anti-Aβ antibody; Immunotherapy; Liposome