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Chronic cholesterol administration to the brain supports complete and long-lasting cognitive and motor amelioration in Huntington’s disease

Evidence that Huntington's disease (HD) is characterized by impaired cholesterol biosynthesis in the brain has led to strategies to increase its level in the brain of the rapidly progressing R6/2 mouse model, with a positive therapeutic outcome. Here we tested the long-term efficacy of chronic...

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Autores principales: Birolini, Giulia, Valenza, Marta, Ottonelli, Ilaria, Talpo, Francesca, Minoli, Lucia, Cappelleri, Andrea, Bombaci, Mauro, Caccia, Claudio, Canevari, Caterina, Trucco, Arianna, Leoni, Valerio, Passoni, Alice, Favagrossa, Monica, Nucera, Maria Rosaria, Colombo, Laura, Paltrinieri, Saverio, Bagnati, Renzo, Duskey, Jason Thomas, Caraffi, Riccardo, Vandelli, Maria Angela, Taroni, Franco, Salmona, Mario, Scanziani, Eugenio, Biella, Gerardo, Ruozi, Barbara, Tosi, Giovanni, Cattaneo, Elena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10463277/
https://www.ncbi.nlm.nih.gov/pubmed/37336430
http://dx.doi.org/10.1016/j.phrs.2023.106823
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author Birolini, Giulia
Valenza, Marta
Ottonelli, Ilaria
Talpo, Francesca
Minoli, Lucia
Cappelleri, Andrea
Bombaci, Mauro
Caccia, Claudio
Canevari, Caterina
Trucco, Arianna
Leoni, Valerio
Passoni, Alice
Favagrossa, Monica
Nucera, Maria Rosaria
Colombo, Laura
Paltrinieri, Saverio
Bagnati, Renzo
Duskey, Jason Thomas
Caraffi, Riccardo
Vandelli, Maria Angela
Taroni, Franco
Salmona, Mario
Scanziani, Eugenio
Biella, Gerardo
Ruozi, Barbara
Tosi, Giovanni
Cattaneo, Elena
author_facet Birolini, Giulia
Valenza, Marta
Ottonelli, Ilaria
Talpo, Francesca
Minoli, Lucia
Cappelleri, Andrea
Bombaci, Mauro
Caccia, Claudio
Canevari, Caterina
Trucco, Arianna
Leoni, Valerio
Passoni, Alice
Favagrossa, Monica
Nucera, Maria Rosaria
Colombo, Laura
Paltrinieri, Saverio
Bagnati, Renzo
Duskey, Jason Thomas
Caraffi, Riccardo
Vandelli, Maria Angela
Taroni, Franco
Salmona, Mario
Scanziani, Eugenio
Biella, Gerardo
Ruozi, Barbara
Tosi, Giovanni
Cattaneo, Elena
author_sort Birolini, Giulia
collection PubMed
description Evidence that Huntington's disease (HD) is characterized by impaired cholesterol biosynthesis in the brain has led to strategies to increase its level in the brain of the rapidly progressing R6/2 mouse model, with a positive therapeutic outcome. Here we tested the long-term efficacy of chronic administration of cholesterol to the brain of the slowly progressing zQ175DN knock-in HD mice in preventing (“early treatment”) or reversing (“late treatment”) HD symptoms. To do this we used the most advanced formulation of cholesterol loaded brain-permeable nanoparticles (NPs), termed hybrid-g7-NPs-chol, which were injected intraperitoneally. We show that one cycle of treatment with hybrid-g7-NPs-chol, administered in the presymptomatic (“early treatment”) or symptomatic (“late treatment”) stages is sufficient to normalize cognitive defects up to 5 months, as well as to improve other behavioral and neuropathological parameters. A multiple cycle treatment combining both early and late treatments (“2 cycle treatment”) lasting 6 months generates therapeutic effects for more than 11 months, without severe adverse reactions. Sustained cholesterol delivery to the brain of zQ175DN mice also reduces mutant Huntingtin aggregates in both the striatum and cortex and completely normalizes synaptic communication in the striatal medium spiny neurons compared to saline-treated HD mice. Furthermore, through a meta-analysis of published and current data, we demonstrated the power of hybrid-g7-NPs-chol and other strategies able to increase brain cholesterol biosynthesis, to reverse cognitive decline and counteract the formation of mutant Huntingtin aggregates. These results demonstrate that cholesterol delivery via brain-permeable NPs is a therapeutic option to sustainably reverse HD-related behavioral decline and neuropathological signs over time, highlighting the therapeutic potential of cholesterol-based strategies in HD patients. DATA AVAILABILITY: This study does not include data deposited in public repositories. Data are available on request to the corresponding authors.
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spelling pubmed-104632772023-08-30 Chronic cholesterol administration to the brain supports complete and long-lasting cognitive and motor amelioration in Huntington’s disease Birolini, Giulia Valenza, Marta Ottonelli, Ilaria Talpo, Francesca Minoli, Lucia Cappelleri, Andrea Bombaci, Mauro Caccia, Claudio Canevari, Caterina Trucco, Arianna Leoni, Valerio Passoni, Alice Favagrossa, Monica Nucera, Maria Rosaria Colombo, Laura Paltrinieri, Saverio Bagnati, Renzo Duskey, Jason Thomas Caraffi, Riccardo Vandelli, Maria Angela Taroni, Franco Salmona, Mario Scanziani, Eugenio Biella, Gerardo Ruozi, Barbara Tosi, Giovanni Cattaneo, Elena Pharmacol Res Article Evidence that Huntington's disease (HD) is characterized by impaired cholesterol biosynthesis in the brain has led to strategies to increase its level in the brain of the rapidly progressing R6/2 mouse model, with a positive therapeutic outcome. Here we tested the long-term efficacy of chronic administration of cholesterol to the brain of the slowly progressing zQ175DN knock-in HD mice in preventing (“early treatment”) or reversing (“late treatment”) HD symptoms. To do this we used the most advanced formulation of cholesterol loaded brain-permeable nanoparticles (NPs), termed hybrid-g7-NPs-chol, which were injected intraperitoneally. We show that one cycle of treatment with hybrid-g7-NPs-chol, administered in the presymptomatic (“early treatment”) or symptomatic (“late treatment”) stages is sufficient to normalize cognitive defects up to 5 months, as well as to improve other behavioral and neuropathological parameters. A multiple cycle treatment combining both early and late treatments (“2 cycle treatment”) lasting 6 months generates therapeutic effects for more than 11 months, without severe adverse reactions. Sustained cholesterol delivery to the brain of zQ175DN mice also reduces mutant Huntingtin aggregates in both the striatum and cortex and completely normalizes synaptic communication in the striatal medium spiny neurons compared to saline-treated HD mice. Furthermore, through a meta-analysis of published and current data, we demonstrated the power of hybrid-g7-NPs-chol and other strategies able to increase brain cholesterol biosynthesis, to reverse cognitive decline and counteract the formation of mutant Huntingtin aggregates. These results demonstrate that cholesterol delivery via brain-permeable NPs is a therapeutic option to sustainably reverse HD-related behavioral decline and neuropathological signs over time, highlighting the therapeutic potential of cholesterol-based strategies in HD patients. DATA AVAILABILITY: This study does not include data deposited in public repositories. Data are available on request to the corresponding authors. Elsevier 2023-08 /pmc/articles/PMC10463277/ /pubmed/37336430 http://dx.doi.org/10.1016/j.phrs.2023.106823 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Birolini, Giulia
Valenza, Marta
Ottonelli, Ilaria
Talpo, Francesca
Minoli, Lucia
Cappelleri, Andrea
Bombaci, Mauro
Caccia, Claudio
Canevari, Caterina
Trucco, Arianna
Leoni, Valerio
Passoni, Alice
Favagrossa, Monica
Nucera, Maria Rosaria
Colombo, Laura
Paltrinieri, Saverio
Bagnati, Renzo
Duskey, Jason Thomas
Caraffi, Riccardo
Vandelli, Maria Angela
Taroni, Franco
Salmona, Mario
Scanziani, Eugenio
Biella, Gerardo
Ruozi, Barbara
Tosi, Giovanni
Cattaneo, Elena
Chronic cholesterol administration to the brain supports complete and long-lasting cognitive and motor amelioration in Huntington’s disease
title Chronic cholesterol administration to the brain supports complete and long-lasting cognitive and motor amelioration in Huntington’s disease
title_full Chronic cholesterol administration to the brain supports complete and long-lasting cognitive and motor amelioration in Huntington’s disease
title_fullStr Chronic cholesterol administration to the brain supports complete and long-lasting cognitive and motor amelioration in Huntington’s disease
title_full_unstemmed Chronic cholesterol administration to the brain supports complete and long-lasting cognitive and motor amelioration in Huntington’s disease
title_short Chronic cholesterol administration to the brain supports complete and long-lasting cognitive and motor amelioration in Huntington’s disease
title_sort chronic cholesterol administration to the brain supports complete and long-lasting cognitive and motor amelioration in huntington’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10463277/
https://www.ncbi.nlm.nih.gov/pubmed/37336430
http://dx.doi.org/10.1016/j.phrs.2023.106823
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