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    Dose-dependent and disease-modifying effects of striatal infusion of cholesterol in Huntington’s disease

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    Type
    Preprint
    Authors
    Birolini, Giulia cc
    Valenza, Marta cc
    Di Paolo, Eleonora
    Vezzoli, Elena
    Talpo, Francesca
    Maniezzi, Claudia
    Caccia, Claudio
    Leoni, Valerio
    Bocchi, Vittoria D.
    Conforti, Paola
    Sogne, Elisa cc
    Petricca, Lara
    Cariulo, Cristina
    Verani, Margherita
    Caricasole, Andrea
    Falqui, Andrea cc
    Biella, Gerardo
    Cattaneo, Elena
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Bioscience Program
    Date
    2020-05-15
    Permanent link to this record
    http://hdl.handle.net/10754/663496
    
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    Abstract
    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:10.1101/2020.05.13.092742
    Publisher
    Cold Spring Harbor Laboratory
    DOI
    10.1101/2020.05.13.092742
    Additional Links
    http://biorxiv.org/lookup/doi/10.1101/2020.05.13.092742
    https://www.biorxiv.org/content/biorxiv/early/2020/05/15/2020.05.13.092742.full.pdf
    ae974a485f413a2113503eed53cd6c53
    10.1101/2020.05.13.092742
    Scopus Count
    Collections
    Biological and Environmental Science and Engineering (BESE) Division; Preprints; Bioscience Program

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