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
