Striatal infusion of cholesterol promotes dose‐dependent behavioral benefits and exerts disease‐modifying effects in Huntington's disease mice
Abstract A variety of pathophysiological mechanisms are implicated in Huntington's disease (HD). Among them, reduced cholesterol biosynthesis has been detected in the HD mouse brain from pre‐symptomatic stages, leading to diminished cholesterol synthesis, particularly in the striatum. In additi...
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| Format: | Article |
| Language: | English |
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Springer Nature
2020-09-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202012519 |
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| author | Giulia Birolini Marta Valenza Eleonora Di Paolo Elena Vezzoli Francesca Talpo Claudia Maniezzi Claudio Caccia Valerio Leoni Franco Taroni Vittoria D Bocchi Paola Conforti Elisa Sogne Lara Petricca Cristina Cariulo Margherita Verani Andrea Caricasole Andrea Falqui Gerardo Biella Elena Cattaneo |
| author_facet | Giulia Birolini Marta Valenza Eleonora Di Paolo Elena Vezzoli Francesca Talpo Claudia Maniezzi Claudio Caccia Valerio Leoni Franco Taroni Vittoria D Bocchi Paola Conforti Elisa Sogne Lara Petricca Cristina Cariulo Margherita Verani Andrea Caricasole Andrea Falqui Gerardo Biella Elena Cattaneo |
| author_sort | Giulia Birolini |
| collection | DOAJ |
| description | Abstract A variety of pathophysiological mechanisms are implicated in Huntington's disease (HD). Among them, reduced cholesterol biosynthesis has been detected in the HD mouse brain from pre‐symptomatic stages, leading to diminished cholesterol synthesis, particularly in the striatum. In addition, systemic injection of cholesterol‐loaded brain‐permeable nanoparticles ameliorates synaptic and cognitive function in a transgenic mouse model of HD. To identify an appropriate treatment regimen and gain mechanistic insights into the beneficial activity of exogenous cholesterol in the HD brain, we employed osmotic mini‐pumps to infuse three escalating doses of cholesterol directly into the striatum of HD mice in a continuous and rate‐controlled manner. All tested doses prevented cognitive decline, while amelioration of disease‐related motor defects was dose‐dependent. In parallel, we found morphological and functional recovery of synaptic transmission involving both excitatory and inhibitory synapses of striatal medium spiny neurons. The treatment also enhanced endogenous cholesterol biosynthesis and clearance of mutant Huntingtin aggregates. These results indicate that cholesterol infusion to the striatum can exert a dose‐dependent, disease‐modifying effect and may be therapeutically relevant in HD. |
| format | Article |
| id | doaj-art-89f06c9b7c8d4934b2e0285e4e423d49 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2020-09-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-89f06c9b7c8d4934b2e0285e4e423d492025-08-20T04:02:55ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-09-01121012010.15252/emmm.202012519Striatal infusion of cholesterol promotes dose‐dependent behavioral benefits and exerts disease‐modifying effects in Huntington's disease miceGiulia Birolini0Marta Valenza1Eleonora Di Paolo2Elena Vezzoli3Francesca Talpo4Claudia Maniezzi5Claudio Caccia6Valerio Leoni7Franco Taroni8Vittoria D Bocchi9Paola Conforti10Elisa Sogne11Lara Petricca12Cristina Cariulo13Margherita Verani14Andrea Caricasole15Andrea Falqui16Gerardo Biella17Elena Cattaneo18Department of Biosciences, University of MilanDepartment of Biosciences, University of MilanDepartment of Biosciences, University of MilanDepartment of Biosciences, University of MilanDepartment of Biology and Biotechnologies, University of PaviaDepartment of Biology and Biotechnologies, University of PaviaUnit of Medical Genetics and Neurogenetics, Fondazione I.R.C.C.S. Istituto Neurologico Carlo BestaSchool of Medicine and Surgery, Monza and Laboratory of Clinical Pathology, Hospital of Desio, ASST‐Monza, University of Milano‐BicoccaUnit of Medical Genetics and Neurogenetics, Fondazione I.R.C.C.S. Istituto Neurologico Carlo BestaDepartment of Biosciences, University of MilanDepartment of Biosciences, University of MilanBiological and Environmental Science & Engineering (BESE) Division, NABLA Lab, King Abdullah University of Science and Technology (KAUST)Neuroscience Unit, Translational and Discovery Research Department, IRBM S.p.ANeuroscience Unit, Translational and Discovery Research Department, IRBM S.p.ANeuroscience Unit, Translational and Discovery Research Department, IRBM S.p.ANeuroscience Unit, Translational and Discovery Research Department, IRBM S.p.ABiological and Environmental Science & Engineering (BESE) Division, NABLA Lab, King Abdullah University of Science and Technology (KAUST)Department of Biology and Biotechnologies, University of PaviaDepartment of Biosciences, University of MilanAbstract A variety of pathophysiological mechanisms are implicated in Huntington's disease (HD). Among them, reduced cholesterol biosynthesis has been detected in the HD mouse brain from pre‐symptomatic stages, leading to diminished cholesterol synthesis, particularly in the striatum. In addition, systemic injection of cholesterol‐loaded brain‐permeable nanoparticles ameliorates synaptic and cognitive function in a transgenic mouse model of HD. To identify an appropriate treatment regimen and gain mechanistic insights into the beneficial activity of exogenous cholesterol in the HD brain, we employed osmotic mini‐pumps to infuse three escalating doses of cholesterol directly into the striatum of HD mice in a continuous and rate‐controlled manner. All tested doses prevented cognitive decline, while amelioration of disease‐related motor defects was dose‐dependent. In parallel, we found morphological and functional recovery of synaptic transmission involving both excitatory and inhibitory synapses of striatal medium spiny neurons. The treatment also enhanced endogenous cholesterol biosynthesis and clearance of mutant Huntingtin aggregates. These results indicate that cholesterol infusion to the striatum can exert a dose‐dependent, disease‐modifying effect and may be therapeutically relevant in HD.https://doi.org/10.15252/emmm.202012519aggregatesbehaviorcholesterolHuntington's diseasesynapses |
| spellingShingle | Giulia Birolini Marta Valenza Eleonora Di Paolo Elena Vezzoli Francesca Talpo Claudia Maniezzi Claudio Caccia Valerio Leoni Franco Taroni Vittoria D Bocchi Paola Conforti Elisa Sogne Lara Petricca Cristina Cariulo Margherita Verani Andrea Caricasole Andrea Falqui Gerardo Biella Elena Cattaneo Striatal infusion of cholesterol promotes dose‐dependent behavioral benefits and exerts disease‐modifying effects in Huntington's disease mice EMBO Molecular Medicine aggregates behavior cholesterol Huntington's disease synapses |
| title | Striatal infusion of cholesterol promotes dose‐dependent behavioral benefits and exerts disease‐modifying effects in Huntington's disease mice |
| title_full | Striatal infusion of cholesterol promotes dose‐dependent behavioral benefits and exerts disease‐modifying effects in Huntington's disease mice |
| title_fullStr | Striatal infusion of cholesterol promotes dose‐dependent behavioral benefits and exerts disease‐modifying effects in Huntington's disease mice |
| title_full_unstemmed | Striatal infusion of cholesterol promotes dose‐dependent behavioral benefits and exerts disease‐modifying effects in Huntington's disease mice |
| title_short | Striatal infusion of cholesterol promotes dose‐dependent behavioral benefits and exerts disease‐modifying effects in Huntington's disease mice |
| title_sort | striatal infusion of cholesterol promotes dose dependent behavioral benefits and exerts disease modifying effects in huntington s disease mice |
| topic | aggregates behavior cholesterol Huntington's disease synapses |
| url | https://doi.org/10.15252/emmm.202012519 |
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