Striatal infusion of cholesterol promotes dose-dependent behavioral benefits and exerts disease-modifying effects in Huntington's disease mice.

Gerardo Biella,Paola Conforti,Elena Cattaneo,Giulia Birolini,Andrea Caricasole,Franco Taroni,Marta Valenza,Claudia Maniezzi,Elena Vezzoli,Elisa Sogne,Margherita Verani,Eleonora Di Paolo,Valerio Leoni,Cristina Cariulo,Francesca Talpo,Lara Petricca,Claudio Caccia,Andrea Falqui,Vittoria D Bocchi

doi:10.15252/emmm.202012519

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 pre‐symptomatic 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.

Highlights

The brain is the most cholesterol-rich organ, accounting for about 25% of the whole body’s cholesterol (Dietschy & Turley, 2004; Dietschy, 2009)
Mini-pumps filled with artificial cerebrospinal fluid (ACSF) or high-dose cholesterol were implanted in wt mice, and behavioral tests were performed
These findings indicate that the high dose of cholesterol enhances 24S-OHC availability and that increased endogenous cholesterol biosynthesis may occur through nuclear translocation of sterol regulatory element binding protein 2 (SREBP2) in glial cells

Summary

Introduction

The brain is the most cholesterol-rich organ, accounting for about 25% of the whole body’s cholesterol (Dietschy & Turley, 2004; Dietschy, 2009). One of the underlying pathophysiological mechanisms is disruption of brain cholesterol biosynthesis due to reduced nuclear translocation of SREBP2 and diminished expression of its downstream target genes in the cholesterol biosynthesis pathway (Valenza et al, 2005, 2015a; Di Pardo et al, 2020) This defect occurs in astrocytes, which are the major producers of cholesterol in the adult brain, with consequent reduction of newly synthetized cholesterol available for neuronal function (Valenza et al, 2010, 2015a). Levels of the brain-derived cholesterol catabolite 24S-hydroxycholesterol (24SOHC) are decreased in brain and blood from HD mice (Valenza et al, 2007b, 2010; Shankaran et al, 2017), post-mortem caudate (Boussicault et al, 2016), plasma of HD patients (Leoni et al, 2008, 2011), as well as in pre-HD manifesting patients who are close to the disease onset (Leoni et al, 2013)

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Conclusion