title: Multifunctional liposomes reduce brain β-amyloid burden and ameliorate memory impairment in Alzheimer's disease mouse models.
abstract: Alzheimer's disease is characterized by the accumulation and deposition of plaques of β-amyloid (Aβ) peptide in the brain. Given its pivotal role, new therapies targeting Aβ are in demand. We rationally designed liposomes targeting the brain and promoting the disaggregation of Aβ assemblies and evaluated their efficiency in reducing the Aβ burden in Alzheimer's disease mouse models. Liposomes were bifunctionalized with a peptide derived from the apolipoprotein-E receptor-binding domain for blood-brain barrier targeting and with phosphatidic acid for Aβ binding. Bifunctionalized liposomes display the unique ability to hinder the formation of, and disaggregate, Aβ assemblies in vitro (EM experiments). Administration of bifunctionalized liposomes to APP/presenilin 1 transgenic mice (aged 10 months) for 3 weeks (three injections per week) decreased total brain-insoluble Aβ1-42 (-33%), assessed by ELISA, and the number and total area of plaques (-34%) detected histologically. Also, brain Aβ oligomers were reduced (-70.5%), as assessed by SDS-PAGE. Plaque reduction was confirmed in APP23 transgenic mice (aged 15 months) either histologically or by PET imaging with [(11)C]Pittsburgh compound B (PIB). The reduction of brain Aβ was associated with its increase in liver (+18%) and spleen (+20%). Notably, the novel-object recognition test showed that the treatment ameliorated mouse impaired memory. Finally, liposomes reached the brain in an intact form, as determined by confocal microscopy experiments with fluorescently labeled liposomes. These data suggest that bifunctionalized liposomes destabilize brain Aβ aggregates and promote peptide removal across the blood-brain barrier and its peripheral clearance. This all-in-one multitask therapeutic device can be considered as a candidate for the treatment of Alzheimer's disease.
authors.affiliation: Departments of Neuroscience.
authors.forename: Claudia
authors.initials: C
authors.lastname: Balducci
authors.affiliation: Department of Health Sciences, University of Milano-Bicocca, 20900 Monza, Italy, and.
authors.forename: Simona
authors.identifier: http://orcid.org/0000-0003-2974-1729
authors.initials: S
authors.lastname: Mancini
authors.affiliation: Department of Health Sciences, University of Milano-Bicocca, 20900 Monza, Italy, and.
authors.forename: Stefania
authors.initials: S
authors.lastname: Minniti
authors.affiliation: Departments of Neuroscience.
authors.forename: Pietro
authors.identifier: http://orcid.org/0000-0001-7415-0739
authors.initials: P
authors.lastname: La Vitola
authors.affiliation: Departments of Neuroscience.
authors.forename: Margherita
authors.initials: M
authors.lastname: Zotti
authors.affiliation: Department of Health Sciences, University of Milano-Bicocca, 20900 Monza, Italy, and.
authors.forename: Giulio
authors.initials: G
authors.lastname: Sancini
authors.affiliation: Department of Health Sciences, University of Milano-Bicocca, 20900 Monza, Italy, and.
authors.forename: Mario
authors.initials: M
authors.lastname: Mauri
authors.affiliation: Molecular Biochemistry and Pharmacology, and.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Cagnotto
authors.affiliation: Molecular Biochemistry and Pharmacology, and.
authors.forename: Laura
authors.identifier: http://orcid.org/0000-0002-3243-0270
authors.initials: L
authors.lastname: Colombo
authors.affiliation: Cardiovascular Research, Institute for Istituto di Ricovero e Cura a Carattere Scientifico/Mario Negri Institute for Pharmacological Research, 20156 Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Fiordaliso
authors.affiliation: Departments of Neuroscience.
authors.forename: Emanuele
authors.identifier: http://orcid.org/0000-0001-7682-0628
authors.initials: E
authors.lastname: Grigoli
authors.affiliation: Molecular Biochemistry and Pharmacology, and.
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
authors.affiliation: MediCity/PET Preclinical Laboratory, Turku PET Centre, University of Turku, 20520 Turku, Finland.
authors.forename: Anniina
authors.initials: A
authors.lastname: Snellman
authors.affiliation: MediCity/PET Preclinical Laboratory, Turku PET Centre, University of Turku, 20520 Turku, Finland.
authors.forename: Merja
authors.initials: M
authors.lastname: Haaparanta-Solin
authors.affiliation: Departments of Neuroscience.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Forloni
authors.affiliation: Department of Health Sciences, University of Milano-Bicocca, 20900 Monza, Italy, and massimo.masserini@unimib.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Masserini
authors.affiliation: Department of Health Sciences, University of Milano-Bicocca, 20900 Monza, Italy, and.
authors.forename: Francesca
authors.initials: F
authors.lastname: Re
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000008:administration & dosage* / Q000378:metabolism; D004195:Disease Models, Animal; D008081:Liposomes / Q000008:administration & dosage* / Q000378:metabolism; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism; D058225:Plaque, Amyloid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011897:Random Allocation
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D008081:Liposomes; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)
keywords: Abeta; Alzheimer; cognitive impairment; liposomes; nanomedicine; oligomers