CHOLESTEROL LOADED NANOPARTICLES INJECTED SYSTEMICALLY REACH THE BRAIN AND LOCALIZE INTO SPECIFIC CELL TYPES

Changes in brain cholesterol biosynthesis have been reported in Huntington’s disease (HD) (Valenza et al., J. Neurosci. 2005; Valenza et al., J. Neurosci. 2010). In particular, biochemical and mass spectrometry analyses have shown reduced levels of several cholesterol precursors in the brains of multiple HD rodent models, leading to reduced content of sterols/cholesterol (Valenza et al., Hum Mol Genet. 2007; Valenza et al., J.Neurosci. 2010). However, others have reported accumulation of sterols in HD brains and cell models, as measured by methods other than mass spectrometry (Trushina et al., Hum Mol Genet. 2006; LuthiCarter et al., PNAS 2010; DelToro et al., J Neurochem. 2010). To test the impact of changes in cholesterol levels in the HD brain, wild-type and HD (R6/2) mice have been injected systemically with poly-lactide-co-glycolide (PLGA) nanoparticles (Nps) loaded with cholesterol and modified with glycopeptides (M-Nps) to obtain high-rate brain delivery (Tosi et al., Nanomedicine 2011). In contrast to unmodified Nps (C-Nps), we show that M-Nps loaded with cholesterol (chol-M-Nps) enter the brain efficiently, and localize in neurons and glial cells both in striatum and cortex within 4 h after intraperitoneal injection while persisting for several weeks both in wild type and HD mice. Additionally, a pilot study suggested that multiple injections ofchol-M-Nps in R6/2 mice positively influence some electrophysiological parameters of striatal medium-sized spiny neurons compared to animals that received empty M-Nps. These preliminary findings suggest that M-Nps may represent a novel and efficient route to deliver molecules (besides cholesterol) into the brain and that cholesterol released by M-Nps may modulate functional parameters in vivo. They also suggest that increasing cholesterol in HD may be beneficial. Further studies will be necessary for defining the impact of abnormalities in cholesterol level in HD pathogenesis and its possible efficacy from a therapeutic standpoint.