title: Cholesterol-loaded nanoparticles ameliorate synaptic and cognitive function in Huntington's disease mice.
abstract: Brain cholesterol biosynthesis and cholesterol levels are reduced in mouse models of Huntington's disease (HD), suggesting that locally synthesized, newly formed cholesterol is less available to neurons. This may be detrimental for neuronal function, especially given that locally synthesized cholesterol is implicated in synapse integrity and remodeling. Here, we used biodegradable and biocompatible polymeric nanoparticles (NPs) modified with glycopeptides (g7) and loaded with cholesterol (g7-NPs-Chol), which per se is not blood-brain barrier (BBB) permeable, to obtain high-rate cholesterol delivery into the brain after intraperitoneal injection in HD mice. We report that g7-NPs, in contrast to unmodified NPs, efficiently crossed the BBB and localized in glial and neuronal cells in different brain regions. We also found that repeated systemic delivery of g7-NPs-Chol rescued synaptic and cognitive dysfunction and partially improved global activity in HD mice. These results demonstrate that cholesterol supplementation to the HD brain reverses functional alterations associated with HD and highlight the potential of this new drug-administration route to the diseased brain.
authors.affiliation: Department of BioSciences, Centre for Stem Cell Research Università degli Studi di Milano, Milan, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Valenza
authors.affiliation: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience Brain Research Institute David Geffen School of Medicine University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Jane Y
authors.initials: JY
authors.lastname: Chen
authors.affiliation: Department of BioSciences, Centre for Stem Cell Research Università degli Studi di Milano, Milan, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Di Paolo
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Ruozi
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Belletti
authors.affiliation: Department of BioSciences, Centre for Stem Cell Research Università degli Studi di Milano, Milan, Italy.
authors.forename: Costanza
authors.initials: C
authors.lastname: Ferrari Bardile
authors.affiliation: Neurological Institute C. Besta, Milan, Italy Laboratory of Clinical Chemistry, Ospedale di Circolo e Fondazione Macchi, Varese, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Leoni
authors.affiliation: Neurological Institute C. Besta, Milan, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Caccia
authors.affiliation: Department of BioSciences, Centre for Stem Cell Research Università degli Studi di Milano, Milan, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Brilli
authors.affiliation: Neurological Institute C. Besta, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Di Donato
authors.affiliation: Neuroscience Institute Cavalieri Ottolenghi Neuroscience Institute of Turin, Orbassano Turin, Italy.
authors.forename: Marina M
authors.initials: MM
authors.lastname: Boido
authors.affiliation: Neuroscience Institute Cavalieri Ottolenghi Neuroscience Institute of Turin, Orbassano Turin, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Vercelli
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Vandelli
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Flavio
authors.initials: F
authors.lastname: Forni
authors.affiliation: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience Brain Research Institute David Geffen School of Medicine University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cepeda
authors.affiliation: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience Brain Research Institute David Geffen School of Medicine University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Levine
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tosi
authors.affiliation: Department of BioSciences, Centre for Stem Cell Research Università degli Studi di Milano, Milan, Italy elena.cattaneo@unimi.it.
authors.forename: Elena
authors.initials: E
authors.lastname: Cattaneo
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D002784:Cholesterol / Q000627:therapeutic use*; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D006816:Huntington Disease / Q000503:physiopathology / Q000628:therapy; D051379:Mice; D053758:Nanoparticles; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
chemical_list: D002784:Cholesterol
keywords: Huntington's disease; cholesterol; cognition; nanoparticles; synapses