Dose-dependent and disease-modifying effects of striatal infusion of cholesterol in Huntington’s disease
Type
PreprintAuthors
Birolini, Giulia
Valenza, Marta

Di Paolo, Eleonora
Vezzoli, Elena
Talpo, Francesca
Maniezzi, Claudia
Caccia, Claudio
Leoni, Valerio
Bocchi, Vittoria D.
Conforti, Paola
Sogne, Elisa

Petricca, Lara
Cariulo, Cristina
Verani, Margherita
Caricasole, Andrea
Falqui, Andrea

Biella, Gerardo
Cattaneo, Elena
KAUST Department
Biological and Environmental Sciences and Engineering (BESE) DivisionBioscience Program
Date
2020-05-15Permanent link to this record
http://hdl.handle.net/10754/663496
Metadata
Show full item recordAbstract
AbstractA 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 pre-symptomatic 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.Citation
Birolini, G., Valenza, M., Di Paolo, E., Vezzoli, E., Talpo, F., Maniezzi, C., … Cattaneo, E. (2020). Dose-dependent and disease-modifying effects of striatal infusion of cholesterol in Huntington’s disease. doi:10.1101/2020.05.13.092742Publisher
Cold Spring Harbor LaboratoryAdditional Links
http://biorxiv.org/lookup/doi/10.1101/2020.05.13.092742https://www.biorxiv.org/content/biorxiv/early/2020/05/15/2020.05.13.092742.full.pdf
ae974a485f413a2113503eed53cd6c53
10.1101/2020.05.13.092742