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

Giulia Birolini; Marta Valenza; Ilaria Ottonelli; Francesca Talpo; Lucia Minoli; Andrea Cappelleri; Mauro Bombaci; Claudio Caccia; Caterina Canevari; Arianna Trucco; Valerio Leoni; Alice Passoni; Monica Favagrossa; Maria Rosaria Nucera; Laura Colombo; Saverio Paltrinieri; Renzo Bagnati; Jason Thomas Duskey; Riccardo Caraffi; Maria Angela Vandelli; Franco Taroni; Mario Salmona; Eugenio Scanziani; Gerardo Rosario Biella; Barbara Ruozi; Giovanni Tosi; Elena F. Cattaneo

doi:10.1016/j.phrs.2023.106823

NeurosciencePharmacological ResearchJun 17, 2023

Peer-reviewed journal article

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

Giulia Birolini iD, Marta Valenza iD, Ilaria Ottonelli iD, Francesca Talpo iD, Lucia Minoli iD, Andrea Cappelleri iD, Mauro Bombaci iD, Claudio Caccia iD, Caterina Canevari iD, Arianna Trucco, Valerio Leoni iD, Alice Passoni iD, Monica Favagrossa iD, Maria Rosaria Nucera iD, Laura Colombo iD, Saverio Paltrinieri iD, Renzo Bagnati iD, Jason Thomas Duskey iD, Riccardo Caraffi iD, Maria Angela Vandelli iD, Franco Taroni iD, Mario Salmona iD, Eugenio Scanziani iD, Gerardo Rosario Biella iD, Barbara Ruozi iD, , Elena F. Cattaneo iD

Abstract

Evidence that Huntingtons 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.

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