TESTING THE EFFICACY OF BRAIN CHOLESTEROL SUPPLEMENTATION AS A POSSIBLE THERAPEUTIC APPROACH FOR HUNTINGTON'S DISEASE

Huntington's disease (HD) is a progressive, fatal, adult-onset, neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene, which encodes an abnormally long polyglutamine repeat in the huntingtin protein. Clinical features of Huntington's disease include progressive motor dysfunction, cognitive decline, and psychiatric disturbance. Currently, the available drugs are used only for symptomatic management of Huntington's disease, but there is no effective therapy. Several studies indicate that brain cholesterol biosynthesis is reduced in several HD rodent models (Valenza et al. 2005) (Valenza et al. 2007) (Valenza et al. 2010) and data from HD patients also suggested a similar reduction (Leoni et al. 2008) (Leoni et al. 2013). This dysfunction may be detrimental for neuronal cells, especially given that locally synthesized cholesterol is implicated in neurite outgrowth, synapses formation and maintenance, synaptic activity and integrity, and optimal neurotransmitter release (Pfrieger et al. 2003). Based on these evidences, we supposed that in vivo supplying of exogenous cholesterol could rescue aspects of neuronal dysfunction. To verify our hypothesis we used different approaches to deliver exogenous cholesterol to the brain of R6/2 mice (Mangiarini et al. 1996), since peripheral cholesterol is not able to cross the blood brain barrier (BBB). In our first study, the delivery of cholesterol via brain-permeable polymeric nanoparticles (g7-NPs- Chol) rescued synaptic communication, protected from cognitive decline and partially improved global activity in HD mice (Valenza et al. 2015). In a second study we tested the efficacy of increasing doses of cholesterol directly infused into mouse brain by osmotic minipumps. Results demonstrated that high amounts of cholesterol have to be delivered to observe both cognitive and motor functional recovery in R6/2 mice. More recently, we started to investigate a third innovative non-invasive strategy based on intranasal delivery of cholesterol and preliminary results will be discussed.