Brain cholesterol biosynthesis and cholesterol levels are reduced in mouse models of Huntington's disease (HD), suggesting that locally synthesized, newly formed cholesterol is less available to neurons. This may be detrimental for neuronal function, especially given that locally synthesized cholesterol is implicated in synapse integrity and remodeling. Here, we used biodegradable and biocompatible polymeric nanoparticles (NPs) modified with glycopeptides (g7) and loaded with cholesterol (g7‐NPs‐Chol), which per se is not blood–brain barrier (BBB) permeable, to obtain high‐rate cholesterol delivery into the brain after intraperitoneal injection in HD mice. We report that g7‐NPs, in contrast to unmodified NPs, efficiently crossed the BBB and localized in glial and neuronal cells in different brain regions. We also found that repeated systemic delivery of g7‐NPs‐Chol rescued synaptic and cognitive dysfunction and partially improved global activity in HD mice. These results demonstrate that cholesterol supplementation to the HD brain reverses functional alterations associated with HD and highlight the potential of this new drug‐administration route to the diseased brain.

In the adult brain, neurons require local cholesterol production, which is supplied by astrocytes through apoE-containing lipoproteins. In Huntington's disease (HD), such cholesterol biosynthesis in the brain is severely reduced. Here we show that this defect, occurring in astrocytes, is detrimental for HD neurons. Astrocytes bearing the huntingtin protein containing increasing CAG repeats secreted less apoE-lipoprotein-bound cholesterol in the medium. Conditioned media from HD astrocytes and lipoprotein-depleted conditioned media from wild-type (wt) astrocytes were equally detrimental in a neurite outgrowth assay and did not support synaptic activity in HD neurons, compared with conditions of cholesterol supplementation or conditioned media from wt astrocytes. Molecular perturbation of cholesterol biosynthesis and efflux in astrocytes caused similarly altered astrocyteneuron cross talk, whereas enhancement of glial SREBP2 and ABCA1 function reversed the aspects of neuronal dysfunction in HD. These findings indicate that astrocyte-mediated cholesterol homeostasis could be a potential therapeutic target to ameliorate neuronal dysfunction in HD. Huntington's disease (HD) is an adult-onset neurodegenerative disorder characterized by cell loss mainly in the striatum and cortex. Its pathophysiology is linked to an expanded CAG repeat in the IT-15 gene, which leads to an elongated polyQ tract in huntingtin (HTT) protein. No disease-modifying treatment is available for HD and novel pathophysiological insights and therapeutic strategies are needed. 1 Lipids are vital to brain health and function. Accordingly, the brain has a local source of cholesterol, 2 and a breakdown of cholesterol synthesis causes brain malformations and impaired cognitive function. 3,4 Cholesterol metabolism is disrupted in HD 5,6 as revealed by transcriptional, biochemical, and mass spectrometry analyses in HD rodent models. 7,8 This dysregulation is linked to a specific action of mutant HTT on sterol-regulatory-element-binding proteins (SREBPs) and on its target genes, whose reduced transcription leads to lower brain cholesterol levels. 7 In HD humans, brain cholesterol homeostasis is affected since pre-symptomatic stages, as determined by measurement of the brain-specific cholesterol catabolite 24-S-hydroxy-cholesterol (24OHC). 9,10 However, it remains unclear how reduced brain cholesterol would become pathological for HD neurons.In adulthood, astrocytes produce cholesterol, which is secreted as a complex with apolipoprotein (apo) E lipoproteins and delivered to neurons. 11,12 Mutant HTT is expressed in glial cells, 13,14 and transgenic mice overexpressing mutant HTT in astrocytes show age-dependent neurological symptoms. 15,16 Additionally, primary astrocytes overexpressing full-length human mutant HTT show reduced mRNA levels of cholesterol biosynthetic genes, along with impaired cellular production and secretion of apoE. 8 Here we employed molecular and cellular tools to test the impact of cholesterol perturbation between astrocytes and neur...

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.

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