Related Experiment Video
Updated: Jul 1, 2026
Stereotaxic Infusion of Oligomeric Amyloid-beta into the Mouse Hippocampus
Published on: June 17, 2015
Striatal infusion of cholesterol promotes dose-dependent behavioral benefits and exerts disease-modifying effects in
Giulia Birolini1,2, Marta Valenza1,2, Eleonora Di Paolo1,2
1Department of Biosciences, University of Milan, Milan, Italy.
Insights
Directly infusing cholesterol into the brain improved cognitive function and motor deficits in Huntington
Area of Science:
- Neuroscience
- Biochemistry
- Genetics
Background:
- Huntington's disease (HD) involves reduced cholesterol biosynthesis, particularly in the striatum, even before symptom onset.
- Systemic cholesterol nanoparticle delivery showed promise in improving synaptic and cognitive function in HD mouse models.
Purpose of the Study:
- To determine an optimal treatment regimen for cholesterol delivery to the HD brain.
- To investigate the mechanistic basis of exogenous cholesterol's therapeutic effects in HD.
Main Methods:
- Osmotic mini-pumps were used to deliver escalating doses of cholesterol directly into the striatum of HD mice.
- Cognitive function, motor deficits, synaptic transmission, and mutant Huntingtin levels were assessed.
Main Results:
- All tested cholesterol doses prevented cognitive decline in HD mice.
- Motor defect amelioration was dependent on the cholesterol dose administered.
- Synaptic transmission, both excitatory and inhibitory, showed recovery in striatal medium spiny neurons.
- Endogenous cholesterol synthesis and clearance of mutant Huntingtin aggregates were enhanced.
Conclusions:
- Direct striatal cholesterol infusion demonstrates a dose-dependent, disease-modifying effect in Huntington's disease models.
- This approach holds therapeutic potential for managing Huntington's disease by restoring cholesterol homeostasis and mitigating pathology.
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.
More Related Videos
08:01Intracerebroventricular Injection of Amyloid-β Peptides in Normal Mice to Acutely Induce Alzheimer-like Cognitive Deficits
Published on: March 16, 2016
07:30HSV-Mediated Transgene Expression of Chimeric Constructs to Study Behavioral Function of GPCR Heteromers in Mice
Published on: July 9, 2016
