B27 Disruption Of Astrocyte-neuron Cholesterol Cross-talk Affects Neuronal Function In Huntington’s Disease

Background Circulating or dietary cholesterol is not able to cross the blood-brain barrier (BBB) and cholesterol homeostasis in brain is thought to depend largely on endogenous biosynthesis. Cholesterol biosynthesis and content are reduced in the brain of several models of Huntington’s disease (HD) (Valenza et al ., 2005; 2007; 2010). This cerebral dysfunction is measurable also in HD patients starting from early disease stages (Leoni et al ., 2008; Leoni et al ., 2013). Aims In the adult brain cholesterol-dependent neuronal activities, such as neurite outgrowth and synaptic properties, mainly rely on the transport of cholesterol from astrocytes on ApoE-containing particles (Mauch et al ., 2001). Cholesterol supply to neurons might be reduced in HD astrocytes by contributing to neuronal dysfunction in HD neurons. Methods and results Here we show that primary astrocytes obtained from R6/2 HD mice and from mouse knock-in Neural Stem (NS) cell lines expressing mutant huntingtin produce and release less cholesterol bound to ApoE-containing lipoproteins into the medium, compared to control astrocytes. Accordingly, conditioned medium from wild-type astrocytes (GCMwt), but not from R6/2 astrocytes (GCMHD) or from wt astrocytes depleted of lipoproteins (GCMwt-delip), is able to compensate the defect in neurite outgrowth and to ameliorate synaptic-related properties in HD neurons. In parallel we established a dose-response relationship between cholesterol application and these parameters. Furthermore, results from gain and loss of function experiments in wt and HD primary astrocytes reinforce the notion of an altered cross-talk between astrocytes and neurons which can be rescued experimentally. Conclusions In conclusion, our results suggest that astrocytes carrying the HD mutation are the major responsible of the cholesterol dysfunction in HD as they contribute to supply less cholesterol to the surrounding neurons.