Impact of reduced glial-derived cholesterol in Huntington’s disease

Huntington's disease (HD) is an autosomal dominant genetic disorder that affects motor coordination and cognitive function. Increasing evidence shows that cholesterol synthesis is reduced in the brains of animal models and patients with HD. In the brain, cholesterol is essential for neuronal function and synaptic activity (i.e., the transmission of signals between neurons). During the course of HD, synaptic activity gradually declines in the striatal and cortical regions of the brain. Cholesterol derived from peripheral cells or introduced by the diet cannot enter the brain due to the blood-brain barrier. Consequently, the brain must produce cholesterol locally. In the adult brain, cholesterol is produced by specialized brain cells known as astrocytes and delivered to neurons via lipoproteins that contain apolipoprotein-E (ApoE). Defects in cholesterol production and transport can alter neuronal function. We hypothesized that reduced cholesterol synthesis in HD astrocytes may affect neurite outgrowth, synaptic activity, and other cholesterol-dependent neuronal activities. We speculate that the effects slowly accumulate, and gradually poison neurons; thus, different brain functions become inadequate at different stages of HD. Here, we propose to explore (i) the extent of alterations in cholesterol exchange between astrocytes and neurons in HD (ii) the consequences of cholesterol alterations for neurite growth and synaptic activity in vitro and in HD models in vivo, and (iii) the development of a genetic strategy for restoring synaptic function in HD mice by increasing astrocyte cholesterol production and/or transport. We expect that the results of this work will determine the relevance of reduced cholesterol biosynthesis in HD, define the molecular targets involved, and reveal whether synaptic dysfunction can be reversed in vivo by increasing the production and/or transport of cholesterol in astrocytes.