Cholesterol‐loaded nanoparticles ameliorate synaptic and cognitive function in Huntington's disease mice

EMBO Molecular Medicine

Marta Valenza²  Jane Y Chen³  Eleonora Di Paolo²  Barbara Ruozi¹  Daniela Belletti¹  Costanza Ferrari Bardile²  Valerio Leoni⁵  Claudio Caccia⁵  Elisa Brilli²  Stefano Di Donato⁵  Marina M Boido⁴  Alessandro Vercelli⁴  Maria A Vandelli¹  Flavio Forni¹  Carlos Cepeda³  Michael S Levine³  Giovanni Tosi¹ 

[1] Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy;Department of BioSciences, Centre for Stem Cell Research, Università degli Studi di Milano, Milan, Italy;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;Neuroscience Institute Cavalieri Ottolenghi, Neuroscience Institute of Turin, Orbassano, Turin, Italy;Neurological Institute C. Besta, Milan, Italy

关键词: cholesterol;    cognition;    Huntington's disease;    nanoparticles;    synapses;   

DOI  :  10.15252/emmm.201505413

来源: Wiley

【 摘 要 】

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.

Synopsis

Cholesterol in brain is largely derived by local synthesis. One affected pathway in Huntington's disease (HD) implicates that reduced production and/or availability of brain cholesterol may be detrimental for neuronal function.

• Polymeric nanoparticles (NPs) loaded with cholesterol, modified with glycopeptides g7 (g7-NPs-Chol) to cross the BBB after systemic injection, have been used to deliver cholesterol to the brain of HD mice.
• These NPs, applied for the first time to a brain disorder, are made of PLGA, which is approved by FDA in various drug delivery systems in humans.
• Systemic administration of g7-NPs-Chol (i) rescued synaptic communication in striatal medium-sized spiny neurons, (ii) prevented cognitive decline, and (iii) restored the levels of proteins that compose the synaptic machinery in HD mice.
• g7-NPs or cholesterol itself did not induce inflammatory response in the periphery, where almost all g7-NPs are localized.

【 授权许可】

CC BY   
© 2015 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.