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Striatal infusion of cholesterol promotes dose‐dependent behavioral benefits and exerts disease‐modifying effects in Huntington's disease mice

Birolini, Giulia, Valenza, Marta, Di Paolo, Eleonora, Vezzoli, Elena, Talpo, Francesca, Maniezzi, Claudia, Caccia, Claudio, Leoni, Valerio, Taroni, Franco, Bocchi, Vittoria D, Conforti, Paola, Sogne, Elisa, Petricca, Lara, Cariulo, Cristina, Verani, Margherita, Caricasole, Andrea, Falqui, Andrea, Biella, Gerardo, Cattaneo, Elena·2020·EMBO Molecular Medicine
DOI 10.15252/emmm.202012519PMC PMC7539329
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Abstract

A 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.

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  • Genetic deletion of SCAP or SREBP2 in astrocytes of adult mice results in cognitive defects.

    “The fact that genetic deletion of SCAP or SREBP2 in astrocytes of adult mice results in cognitive defects 38,39 confirms the role of astrocytes in memory and cognition in vivo, and that altered cross-talk between astrocytes and neurons at synaptic contacts may contribute to cognitive disturbances 40 .”

    From SREBP2 gene therapy targeting striatal astrocytes ameliorates Huntington’s disease phenotypes (2021) · cites this paper as [38]

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Metadata

Authors
Birolini, G., Valenza, M., Di Paolo, E., Vezzoli, E., Talpo, F., Maniezzi, C., Caccia, C., Leoni, V., Taroni, F., Bocchi, V. D., Conforti, P., Sogne, E., Petricca, L., Cariulo, C., Verani, M., Caricasole, A., Falqui, A., Biella, G., & Cattaneo, E.
ORCID
Venue
EMBO Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2020-09-22
Volume
12
Issue
10
ISSN
  • 1757-4676
  • 1757-4684
DOI
10.15252/emmm.202012519
PMC
PMC7539329
Cited by
27
References
10
Language
en
Licence
Funders
  • EC|FP7|FP7 Health (305121)
  • EU Joint Programme – Neurodegenerative Disease Research (643417)
  • Fondazione Telethon (GGP17102)
  • KAUST Baseline funding
  • the Italian Ministry of Education, University and Research
  • Fondazione Umberto Veronesi

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