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

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 ratecontrolled 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.

SREBP2 delivery to striatal astrocytes normalizes transcription of cholesterol biosynthesis genes and ameliorates pathological features in Huntington’s Disease

“…As expected, the steady-state levels of all cholesterol precursors were reduced in the striata of R6/2-Tom mice compared with wt-Tom mice (Fig. 2H–J) 19,20,27,28 . hSREBP2 delivery in glial cells, although unable to affect lanosterol and lathosterol levels (Fig.…”

“…We show that unilateral striatal AAV-delivery of SREBP2 in glial cells is sufficient to completely rescue cognitive decline in R6/2 mice. Similar data were obtained upon cholesterol delivery to the brain of this mouse model via brain-permeable polymeric nanoparticles or mini-pumps 27,28 . 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 .…”

“…At the neuropathological level, increased hSREBP2 in the striatum of R6/2 mice reduced the number and size of muHTT aggregates, supporting the notion that enhanced cholesterol biosynthesis may participate in inducing clearance pathways, as we recently showed in the striata of HD mice following striatal infusion of cholesterol through osmotic mini-pumps 28 . The fact that in the current study the transgene was delivered to astrocytes suggests that clearance may also occur by a non-cell autonomous mechanism.…”

“…These results are in agreement with our recent work that evaluated the effect of three escalating doses of cholesterol infused directly into the striata of R6/2 mice through osmotic mini-pumps. Indeed, we demonstrated that all three doses prevented cognitive defects, while only the highest dose attenuated motor phenotypes 28 .…”