Cholesterol-laden brain-permeable nanoparticles support long-lasting cognitive recovery and motor amelioration in the slow-progressing zQ175DN mouse model of Huntington’s Disease

Huntington’s disease (HD) has been linked to reduced synthesis of cholesterol in the brain. Its exogenous delivery to the brain has been shown to be beneficial in the rapidly progressing R6/2 mouse model. Here we used an advanced formulation of brain-permeable nanoparticles (NPs) loaded with cholesterol and called hybrid-g7-NPs-chol, to explore the long-term therapeutical potential of cholesterol administration to the brain of the slow-progressing zQ175DN knock-in HD mouse model. We show that one cycle treatment with hybrid-g7-NPs-chol, administered in the pre-symptomatic or symptomatic phases, is sufficient to completely normalize cognitive defects up to 5 months, as well as to improve other behavioral and neuropathological parameters. Instead, two cycles of hybrid-g7-NPs-chol are needed to achieve long-lasting therapeutic benefits for 12 months without severe inflammatory side-effects. Sustained cholesterol 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. These results show that cholesterol delivery via brain-permeable NPs is a safe and versatile therapeutic option for lastingly reversing HD-related behavioral decline and neuropathological signs, highlighting the translational potential of cholesterol-based strategies in HD patients.