title: Multifunctional liposomes interact with Abeta in human biological fluids: Therapeutic implications for Alzheimer's disease.
abstract: The accumulation of extracellular amyloid beta (Abeta42) both in brain and in cerebral vessels characterizes Alzheimer's disease (AD) pathogenesis. Recently, the possibility to functionalize nanoparticles (NPs) surface with Abeta42 binding molecules, making them suitable tools for reducing Abeta42 burden has been shown effective in models of AD. Aim of this work consisted in proving that NPs might be effective in sequestering Abeta42 in biological fluids, such as CSF and plasma. This demonstration is extremely important considering that these Abeta42 pools are in continuum with the brain parenchyma with drainage of Abeta from interstitial brain tissue to blood vessel and plasma. In this work, liposomes (LIP) were functionalized as previously shown in order to promote high-affinity Abeta binding, i.e., either with, phosphatidic acid (PA), or a modified Apolipoprotein E-derived peptide (mApo), or with a curcumin derivative (TREG); Abeta42 levels were determined by ELISA in CSF and plasma samples. mApo-PA-LIP (25 and 250 μM) mildly albeit significantly sequestered Abeta42 proteins in CSF samples obtained from healthy subjects (p < 0.01). Analogously a significant binding (∼20%) of Abeta42 (p < 0.001) was demonstrated following exposure to all functionalized liposomes in plasma samples obtained from selected AD or Down's syndrome patients expressing high levels of Abeta42. The same results were obtained by quantifying Abeta42 content after removal of liposome-bound Abeta by using gel filtration chromatography or ultracentrifugation on a discontinuous sucrose density gradient. In conclusion, we demonstrate that functionalized liposomes significantly sequester Abeta42 in human biological fluids. These data may be critical for future in vivo administration tests using NPs for promoting sink effect.
authors.affiliation: Laboratory of Neurobiology, School of Medicine and Surgery and Milan Center for Neuroscience, University of Milano-Bicocca, Monza, Italy. Electronic address: elisa.conti@unimib.it.
authors.forename: Elisa
authors.initials: E
authors.lastname: Conti
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza and Nanomedicine Center NANOMIB, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Gregori
authors.affiliation: Laboratory of Neurobiology, School of Medicine and Surgery and Milan Center for Neuroscience, University of Milano-Bicocca, Monza, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Radice
authors.affiliation: Laboratory of Neurobiology, School of Medicine and Surgery and Milan Center for Neuroscience, University of Milano-Bicocca, Monza, Italy; Neurology, San Gerardo Hospital, Monza, Italy.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Da Re
authors.affiliation: Laboratory of Neurobiology, School of Medicine and Surgery and Milan Center for Neuroscience, University of Milano-Bicocca, Monza, Italy.
authors.forename: Denise
authors.initials: D
authors.lastname: Grana
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza and Nanomedicine Center NANOMIB, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Re
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza and Nanomedicine Center NANOMIB, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Salvati
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza and Nanomedicine Center NANOMIB, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Masserini
authors.affiliation: Laboratory of Neurobiology, School of Medicine and Surgery and Milan Center for Neuroscience, University of Milano-Bicocca, Monza, Italy; Neurology, San Gerardo Hospital, Monza, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Ferrarese
authors.affiliation: Laboratory of Neurobiology, School of Medicine and Surgery and Milan Center for Neuroscience, University of Milano-Bicocca, Monza, Italy.
authors.forename: Chiara Paola
authors.initials: CP
authors.lastname: Zoia
authors.affiliation: Laboratory of Neurobiology, School of Medicine and Surgery and Milan Center for Neuroscience, University of Milano-Bicocca, Monza, Italy; Neurology, San Gerardo Hospital, Monza, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Tremolizzo
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood* / Q000134:cerebrospinal fluid*; D016229:Amyloid beta-Peptides / Q000097:blood* / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D005260:Female; D006801:Humans; D008081:Liposomes / Q000378:metabolism*; D008297:Male; D010446:Peptide Fragments / Q000097:blood* / Q000134:cerebrospinal fluid*
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D008081:Liposomes; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's disease; Beta amyloid; Liposomes; Sink effect