I17 Sustained benefits of brain-permeable cholesterol-loaded nanoparticles in zQ175DN mouse model. (12th September 2022)

• Record Type: Journal Article
• Authors: Valenza, Marta; Birolini, Giulia; Ottonelli, Ilaria; Talpo, Francesca; Passoni, Alice; Favagrossa, Monica; Colombo, Laura; Caraffi, Riccardo; Caccia, Claudio; Leoni, Valerio; Taroni, Franco; Cappelleri, Andrea; Minoli, Lucia; Paltrinieri, Saverio; Scanziani, Eugenio; Ruozi, Barbara; Salmona, Mario; Biella, Gerardo; Tosi, Giovanni; Cattaneo, Elena
• Is Part Of: Journal of neurology, neurosurgery and psychiatry. Volume 93(2022)Supplement 1
• Page Start: A90
• Page End: A90
• Publication Date: 2022-09-12
• Subjects: Cholesterol -- nanoparticles -- zQ175DN -- behaviour; Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Psychiatry -- Periodicals; 616.8
• DOI: 10.1136/jnnp-2022-ehdn.243
• Languages: English
• ISSNs: 0022-3050

Abstract

Abstract : Background: Huntington's disease (HD) is associated with reduced synthesis of brain cholesterol (chol) and mounting evidence highlights the concept that strategies aimed at delivering chol to the brain is beneficial in HD. More recently, we demonstrated that the systemic administration of the most advanced formulation of brain-permeable chol-loaded nanoparticles (hybrid-g7-NPs-chol) prevents cognitive decline and ameliorates some motor defects in the fast-progressing R6/2 mouse model. Aims and Methods: Here we employed the slowly progressing zQ175DN (delta neo) heterozygous (het) knock-in HD mouse model to explore the long-term potential of hybrid-g7-NPs-chol through the evaluation of cognitive and motor tasks, electrophysiological analysis, and neuropathological assays. Response of the immune system and histological analysis in all organs were also examined to explore potential side effects. Results: By testing different treatment regimens, we demonstrated that one cycle of hybrid-g7-NPs-chol, either at pre-symptomatic or symptomatic stage, is sufficient to prevent or normalize several behavioral defects for a long time. More cycles of hybrid-g7-NPs-chol are needed to obtain lasting and complete therapeutical benefits without long-term side effects. Sustained chol delivery to the brain of zQ175DN mice also reduces mutant Huntingtin aggregates both in striatum and cortex and completely normalizes glutamatergic communication in the striatal medium spiny neurons compared to saline-treated HD mice. Conclusions: Our results show that chol delivery through brain-permeable nanoparticles is a safe and versatile therapeutic option to reverse behavioral decline and HD-related neuropathological signs in a long-term manner, highlighting the potential to translate cholesterol-based strategies in HD patients.