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 presymptomatic 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.

Insights into kinetics, release, and behavioral effects of brain-targeted hybrid nanoparticles for cholesterol delivery in Huntington’s disease

“…We have recently demonstrated that a therapeutically relevant dose of cholesterol delivered to the striatum through osmotic mini-pumps indirectly stimulated endogenous cholesterol synthesis, leading to the reversal of both motor and cognitive abnormalities in HD mice [19]. In contrast, lower doses delivered to the striatum through osmotic mini-pumps [19] or to the brain via PLGA-g7-NPs-chol [13] led to a complete rescue of cognitive decline without significant change in endogenous brain cholesterol biosynthesis or in motor performance.…”

“…Previous studies pointed out the benefits of strategies aimed at delivering cholesterol to the HD brain [13, 19], but defining the dose of cholesterol that reaches the brain is critical to a complete understanding of the power and limits of the approach. With the aim of developing a new and non-invasive strategy closer to clinical application, hybrid-g7-NPs-chol were produced with improved chemical and physical properties and increased cholesterol content [21].…”

“…In a subsequent study, cholesterol was infused for 4 weeks into the striatum of HD mice through osmotic mini-pumps, a well-characterized system for controlled drug delivery. This led to the identification of the optimal dose of cholesterol needed to restore synaptic and neuropathological features and reverse motor and cognitive abnormalities in HD mice [19]. Recently, the effectiveness of nose-to-brain delivery of cholesterol to the HD brain has also been tested [20].…”

“…In the first study with PLGA-g7-NPs-chol, the amount of cholesterol delivered to the brain was sub-optimal compared with the dose identified with osmotic mini-pumps. In particular, this kind of NPs was estimated to deliver to the brain about 2 μg of cholesterol in each systemic injection [13], while about 13 μg of cholesterol per day were infused in the striatum with mini-pumps, enabling the maximum benefit in HD mice following 4 weeks of treatment [19].…”

“…The maximal percentages of cholesterol present in hybrid-g7-NPs-chol MIX-N and MIX-SE were 32.7 ± 2% and 41.5 ± 1.5%, respectively, reaching a cholesterol content which is around 40 times higher than that of PLGA-g7-NPs-chol [13]. This drug delivery system is therefore expected to deliver to the HD brain a therapeutic dose of cholesterol closer to that identified with the osmotic mini-pumps [19], while being less invasive and more translatable. This study therefore aimed to investigate the distribution of hybrid-g7-NPs-chol in different brain regions, peripheral tissues, and the circulation, and the kinetics of cholesterol release, the benefits to animals’ behavior.…”